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Obstetrician & Gynecologist (OB/GYN)
20 years of experience
Accepting new patients
Video profile

Credentials

Education ?

Medical School Score
West Virginia University (1992)
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Awards & Distinctions ?

Awards  
Patients' Choice Award (2012 - 2015)
Compassionate Doctor Recognition (2012 - 2015)
On-Time Doctor Award (2014 - 2015)
Associations
American Board of Obstetrics and Gynecology

Affiliations ?

Dr. Thompson is affiliated with 2 hospitals.

Hospital Affiliations

Score

Rankings

  • Beaufort Memorial Hospital
    955 Ribaut Rd, Beaufort, SC 29902
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  • Bluffton Medical Services
  • Publications & Research

    Dr. Thompson has contributed to 112 publications.
    Title Genes in the Insulin and Insulin-like Growth Factor Pathway and Odds of Metachronous Colorectal Neoplasia.
    Date July 2011
    Journal Human Genetics
    Excerpt

    Insulin and insulin-like growth factor (IGF) genes are implicated in colorectal carcinogenesis. Gene-by-gene interactions that influence the insulin/IGF pathways were hypothesized as modifiers of colorectal neoplasia risk. We built a classification tree to detect interactions in 18 IGF and insulin pathway-related genes and metachronous colorectal neoplasia among 1,439 subjects pooled from two chemoprevention trials. The probability of colorectal neoplasia was greatest (71.8%) among carriers of any A allele for rs7166348 (IGF1R) and AA genotype for rs1823023 (PIK3R1). In contrast, carriers of any A at rs7166348 (IGF1R), any G for the PIK3R1 variant, and AA for rs10426094 (INSR) had the lowest probability (14.3%). Logistic regression modeling showed that any A at rs7166348 (IGF1R) with the AA genotype at rs1823023 (PIK3R1) conferred the highest odds of colorectal neoplasia (OR 3.7; 95% CI 2.2-6.5), compared with carriage of GG at rs7166348 (IGF1R). Conversely, any A at rs7166348 (IGFR1), any G allele at rs1823023 (PIK3R1), and the AA genotype at rs10426094 (INSR) conferred the lowest odds (OR 0.22; 95% CI 0.07-0.66). Stratifying the analysis by parent study and intervention arm showed highly consistent trends in direction and magnitude of associations, with preliminary evidence of genotype effects on measured IGF-1 levels in a subgroup of subjects. These results were compared to those from multifactor dimensionality reduction, which identified different single nucleotide polymorphisms in the same genes (INSR and IGF1R) as effect modifiers for colorectal neoplasia. These results support a role for genetic interactions in the insulin/IGF pathway genes in colorectal neoplasia risk.

    Title What Can We Learn About Disease Etiology from Case-case Analyses? Lessons from Breast Cancer.
    Date February 2011
    Journal Cancer Epidemiology, Biomarkers & Prevention : a Publication of the American Association for Cancer Research, Cosponsored by the American Society of Preventive Oncology
    Title Relation of Serotonin Transporter Genetic Variation to Efficacy of Escitalopram for Generalized Anxiety Disorder in Older Adults.
    Date February 2011
    Journal Journal of Clinical Psychopharmacology
    Excerpt

    Generalized anxiety disorder (GAD) is common in older adults and can be treated with selective serotonin reuptake inhibitors (SSRIs). Genetic variation in the serotonin transporter gene promoter region is posited to be associated with SSRI efficacy: 2 polymorphisms (5-HTTLPR S/L and rs25531 g/a) form a haplotype with the La combination having higher transcription activity than other haplotypes. We hypothesized that GAD patients with no La haplotypes (La⁻) have lower SSRI treatment efficacy than those with 1 to 2 La haplotypes (La+).

    Title Oral Selenium Supplementation Has No Effect on Prostate-specific Antigen Velocity in Men Undergoing Active Surveillance for Localized Prostate Cancer.
    Date December 2010
    Journal Cancer Prevention Research (philadelphia, Pa.)
    Excerpt

    The Nutritional Prevention of Cancer trial showed a 52% lower incidence of prostate cancer in men supplemented with selenium. As a result, our study was designed to assess whether selenium supplementation attenuates the progression of prostate cancer. A phase 2 randomized, double-blind, placebo-controlled clinical trial was conducted in men with localized nonmetastatic prostate cancer who had elected to forgo active treatment and be followed by active surveillance. A total of 140 men were randomized to placebo (n = 46), 200 microg/d (n = 47), or 800 microg/d (n = 47) selenium p.o. (as selenized yeast) and followed every 3 months for up to 5 years. Prostate-specific antigen (PSA) velocity was used as a marker of prostate cancer progression and was estimated using mixed-effects regression. Adjusting for age, body mass index, baseline selenium, smoking, baseline PSA, race, PSA method, and Gleason score, PSA velocities for the 200 microg/d and 800 microg/d treatment groups were not statistically significantly different from placebo (P = 0.32 and P = 0.61, respectively). In the highest quartile of baseline selenium, men supplemented with 800 microg selenium showed statistically significantly higher PSA velocity as compared with placebo (P = 0.018). Selenium supplementation did not show a protective effect on PSA velocity in subjects with localized prostate cancer. On the contrary, supplementation with high-dose selenium was observed to be a risk factor for increased PSA velocity in men with high baseline plasma selenium concentrations.

    Title Ornithine Decarboxylase-1 Polymorphism, Chemoprevention with Eflornithine and Sulindac, and Outcomes Among Colorectal Adenoma Patients.
    Date October 2010
    Journal Journal of the National Cancer Institute
    Excerpt

    The ornithine decarboxylase-1 (ODC1) polymorphism at position +316 affects binding by transcriptional activators and repressors and modulates the risk of metachronous colorectal adenomas, particularly in association with aspirin use. We investigated the effects of ODC1 after treatment with difluoromethylornithine (eflornithine)/sulindac or placebo. Two hundred twenty-eight colorectal adenoma patients in a randomized phase III trial were genotyped for ODC1. We used Wilcoxon rank sums tests on non-normally distributed continuous variables across two genotype groups, χ(2) or Fisher exact test to assess the association between baseline categorical variables and genotype group, and log binomial regression for the primary (adenoma recurrence) and secondary outcomes (tissue polyamine response, cardiovascular toxicity, gastrointestinal toxicity, and ototoxicity). All statistical tests were two-sided. In binomial regression models with variables age, sex, race, aspirin use, treatment, and ODC1 genotype, treatment was the only statistically significant factor associated with differences in adenoma recurrence or tissue polyamine response. A statistically significant interaction was detected between ODC1 genotype and treatment with respect to adenoma recurrence (placebo group: GG, 50%, AA/GA: 34%; treatment group: GG, 11%, AA/GA, 21%; P(interaction) = .038). Excess ototoxicity was observed among ODC1 AA patients receiving treatment, but the interaction of genotype and treatment on ototoxicity was not statistically significant (P = .45).

    Title The Excite Stroke Trial: Comparing Early and Delayed Constraint-induced Movement Therapy.
    Date October 2010
    Journal Stroke; a Journal of Cerebral Circulation
    Excerpt

    Although constraint-induced movement therapy (CIMT) has been shown to improve upper extremity function in stroke survivors at both early and late stages after stroke, the comparison between participants within the same cohort but receiving the intervention at different time points has not been undertaken. Therefore, the purpose of this study was to compare functional improvements between stroke participants randomized to receive this intervention within 3 to 9 months (early group) to participants randomized on recruitment to receive the identical intervention 15 to 21 months after stroke (delayed group).

    Title Association Between Polymorphic Variation in Vdr and Rxra and Circulating Levels of Vitamin D Metabolites.
    Date September 2010
    Journal The Journal of Steroid Biochemistry and Molecular Biology
    Excerpt

    The vitamin D metabolite 1,25(OH)2D is the bioactive ligand of the vitamin D receptor (VDR). VDR forms a heterodimer with the retinoid X receptors (RXRs) that when bound to ligand influences the transcriptional control of genes that regulate circulating levels of vitamin D metabolites. Whether genetic variation in VDR or RXRA affects circulating levels of 1,25(OH)2D or 25(OH)D has not been established. We used a single nucleotide polymorphism (SNP) tagging approach to evaluate the association between SNPs in VDR and RXRA and serum levels of 1,25(OH)2D and 25(OH)D. A total of 42 tagSNPs in VDR and 32 in RXRA were analyzed in a sample of 415 participants. Principal components analyses revealed a gene-level association between RXRA and serum 1,25(OH)2D concentrations (P=0.01), but not 25(OH)D. No gene-level association was found for VDR with either serum biomarker. At the single-SNP level, a significant positive trend was observed for increasing 1,25(OH)2D levels with each additional copy of the A allele for RXRA SNP rs9409929 (P-trend=0.003). After a multiple comparisons adjustment, no individual SNP in VDR or RXRA was significantly associated with either outcome. These results demonstrate an association between genetic variation in RXRA and 1,25(OH)2D serum concentrations.

    Title Levels of Rectal Mucosal Polyamines and Prostaglandin E2 Predict Ability of Dfmo and Sulindac to Prevent Colorectal Adenoma.
    Date September 2010
    Journal Gastroenterology
    Excerpt

    Combination of polyamine and prostaglandin E2 (PGE2)-synthesis inhibitors reduced the risk of colorectal adenoma (CRA) by 70% in patients who received polypectomies. We studied effects of the combination of difluoromethylornithine (DFMO) and sulindac on biomarkers and investigated factors that modify their efficacy.

    Title Genetic Variation in the Retinoid X Receptor and Calcium-sensing Receptor and Risk of Colorectal Cancer in the Colon Cancer Family Registry.
    Date September 2010
    Journal Carcinogenesis
    Excerpt

    Genetic variants in the calcium/vitamin D metabolic pathway may be related to risk for colorectal cancer. While several investigations of vitamin D receptor (VDR) polymorphisms and colorectal cancer have been conducted, no studies to date have evaluated the association of genetic variation in the heterodimer partner for VDR, the retinoid X receptor (RXR). Another important gene in this pathway is the calcium-sensing receptor (CASR). Employing a discordant-sibship case-control design, we examined the association between single nucleotide polymorphisms (SNPs) in RXRA and CASR and risk for colorectal cancer overall and by colorectal subsite and microsatellite instability (MSI) status using data from the Colon Cancer Family Registry. No gene-level relationships between RXRA or CASR and colorectal cancer overall were observed. However, for RXRA SNP rs7861779, a high-interest SNP selected for study a priori, there was a statistically significantly increased risk for proximal colorectal cancer among those with at least one A allele [odds ratio (OR) = 1.42; 95% confidence interval (CI) = 1.03-1.97]. Another selected RXRA SNP, rs12004589, was significantly associated with risk of MSI-high cancers (OR = 2.27; 95% CI = 1.13-4.56). Additionally, CASR SNP rs1801726 was significantly associated with a reduced risk for rectal cancer (OR = 0.53; 95% CI = 0.29-0.96). These results provide support that RXRA SNPs rs7861779 and rs12004589 and CASR SNP rs1801726 may be important markers for colorectal neoplasia. Further work is needed to elucidate their role in the carcinogenic pathway.

    Title Effect of Astaxanthin Supplementation on Inflammation and Cardiac Function in Balb/c Mice.
    Date August 2010
    Journal Anticancer Research
    Excerpt

    Astaxanthin is an antioxidant with immunomodulatory, anti-inflammatory and anticancer properties. This study evaluated the use of dietary astaxanthin to decrease oxidative stress and improve cardiac function, thereby providing a potential cardioprotective supplement. Female BALB/c mice (8 weeks of age) were fed a semi-synthetic diet containing 0, 0.02 or 0.08% astaxanthin for 8 weeks. Cardiac function was assessed by echocardiography bi-weekly, and blood and tissue samples were collected at 8 weeks. Plasma astaxanthin concentrations increased (p<0.05) dose-dependently to 0.5 and 4 mumol/l in the astaxanthin-supplemented mice. Blood glutathione concentrations and lymphocyte mitochondrial membrane potential were not significantly affected by astaxanthin treatment. However, mice fed 0.08% astaxanthin had higher (p<0.05) heart mitochondrial membrane potential and contractility index compared to the control group. These results support the possible use of dietary astaxanthin for cardiac protection.

    Title Race and Ethnicity and Breast Cancer Outcomes in an Underinsured Population.
    Date August 2010
    Journal Journal of the National Cancer Institute
    Excerpt

    The disparity in breast cancer mortality between African American women and non-Hispanic white women has been the subject of increased scrutiny. Few studies have addressed these differences in the setting of equal access to health care. We compared the breast cancer outcomes of underinsured African American and non-Hispanic white patients who were treated at a single institution.

    Title Effect of Dietary Astaxanthin at Different Stages of Mammary Tumor Initiation in Balb/c Mice.
    Date August 2010
    Journal Anticancer Research
    Excerpt

    The effects of astaxanthin on tumor growth, cardiac function and immune response in mice were studied. Female BALB/c mice were fed a control diet (diet C) for 8 weeks, 0.005% astaxathin for 8 weeks (diet A), or diet C for weeks 1-5 followed by diet A thereafter (diet CA). Mice were injected with a mammary tumor cell line on day 7 and tumor growth was measured daily. Mice fed diet A had extended tumor latency and lower tumor volume (p<0.05). Interestingly, those fed diet CA showed the fastest tumor growth. Astaxanthin feeding elevated plasma astaxanthin concentrations; there was no difference in plasma astaxanthin between mice fed CA and those fed A. Mice fed diet A, but not CA, had a higher (p<0.05) natural killer cell subpopulation and plasma interferon-gamma concentration compared to those fed diet C. Astaxanthin delayed tumor growth and modulated immune response, but only when astaxanthin was given before tumor initiation. This suggests that an adequate blood astaxanthin status is needed to protect against tumor initiation; conversely, astaxanthin supplementation after tumor initiation may be contraindicated.

    Title The Halt Polycystic Kidney Disease Trials: Design and Implementation.
    Date May 2010
    Journal Clinical Journal of the American Society of Nephrology : Cjasn
    Excerpt

    Two HALT PKD trials will investigate interventions that potentially slow kidney disease progression in hypertensive autosomal dominant polycystic kidney disease (ADPKD) patients. Studies were designed in early and later stages of ADPKD to assess the impact of intensive blockade of the renin-angiotensin-aldosterone system and level of BP control on progressive renal disease. Design, settings, participants, and measurements: PKD-HALT trials are multicenter, randomized, double-blind, placebo-controlled trials studying 1018 hypertensive ADPKD patients enrolled over 3 yr with 4 to 8 yr of follow-up. In study A, 548 participants, estimated GFR (eGFR) of >60 ml/min per 1.73 m(2) were randomized to one of four arms in a 2-by-2 design: combination angiotensin converting enzyme inhibitor (ACEi) and angiotensin receptor blocker (ARB) therapy versus ACEi monotherapy at two levels of BP control. In study B, 470 participants, eGFR of 25 to 60 ml/min per 1.73 m2 compared ACEi/ARB therapy versus ACEi monotherapy, with BP control of 120 to 130/70 to 80 mmHg. Primary outcomes of studies A and B are MR-based percent change kidney volume and a composite endpoint of time to 50% reduction of baseline estimated eGFR, ESRD, or death, respectively.

    Title Effect of Aspirin, Other Nsaids, and Statins on Psa and Psa Velocity.
    Date May 2010
    Journal The Prostate
    Excerpt

    Aspirin, other non-steroidal anti-inflammatory drugs (NSAIDs), and statins have been associated with lower risk of prostate cancer and its progression, though results have been inconsistent.

    Title Expression of Gastric Pyloric Mucin, Muc6, in Colorectal Serrated Polyps.
    Date April 2010
    Journal Modern Pathology : an Official Journal of the United States and Canadian Academy of Pathology, Inc
    Excerpt

    Serrated polyps of the colorectal mucosa represent a heterogeneous and controversial taxonomic category with variation in histopathological, molecular, and immunohistochemical characteristics and with an incomplete understanding of pathogenesis. A previous study reported that the expression of gastric pyloric-type mucin, MUC6, characterized sessile serrated adenomas. We therefore evaluated the expression of MUC6 in serrated polyps identified among 2502 participants in a Phase III chemoprevention trial within the Arizona Cancer Center Colorectal Cancer Prevention Trials Program and characterized the associated histopathological features and location. We carried out immunohistochemistry for MUC6 on 146 serrated lesions and 87 conventional tubular adenomas, and assessed the percentage of cells with expression and the grade of staining intensity. In all 92 hyperplastic polyps, 43 sessile serrated adenomas, and 11 traditional serrated adenomas were included. Polyps ranged in size from 1-150 mm. The association of MUC6 staining with serrated polyp category was evaluated using classification and regression tree (CART) analysis and two-sided Fisher's exact test. A total of 53% of sessile serrated adenomas (n=23), 17% of hyperplastic polyps (n=16), and 18% of traditional serrated adenomas (n=2), but none of 87 tubular adenomas, expressed MUC6. Expression was limited to the lower crypts in all serrated polyps. The extent of positive staining ranged from 2-100% of crypt cells and was independent of the histopathological type. MUC6 expression had relatively high specificity for sessile serrated adenoma (82%) but low sensitivity (54%). In CART analysis, proximal location was found to be the best partitioning factor for MUC6, followed by classification as sessile serrated adenoma. We conclude that MUC6 expression is strongly associated with proximal location of serrated polyps, but only has modest utility as a tissue biomarker for sessile serrated adenoma.

    Title Genetic Polymorphisms in Vitamin D Receptor Vdr/rxra Influence the Likelihood of Colon Adenoma Recurrence.
    Date April 2010
    Journal Cancer Research
    Excerpt

    Low circulating levels of vitamin D affect colorectal cancer risk. The biological actions of the hormonal form of vitamin D, 1,25(OH)(2)D(3), are mediated by the vitamin D receptor (VDR), which heterodimerizes with retinoid X receptors (RXR). Using a single nucleotide polymorphism (SNP) tagging approach, we assessed the association between genetic variations in RXRA and VDR and odds of recurrent (metachronous) colorectal neoplasia in a pooled population of two studies. A total of 32 tag SNPs in RXRA and 42 in VDR were analyzed in 1,439 participants. A gene-level association was observed for RXRA and any (P = 0.04) or proximal (P = 0.03) metachronous neoplasia. No gene-level associations were observed for VDR, nor was any single SNP in VDR related to any metachronous adenoma after correction for multiple comparisons. In contrast, the association between RXRA SNP rs7861779 and proximal metachronous neoplasia was of borderline statistical significance [odds ratio (OR), 0.68; 95% confidence interval (95% CI), 0.53-0.86; unadjusted P = 0.001; adjusted P = 0.06], including when observed independently in each individual study. Haplotypes within linkage blocks of RXRA support an approximately 30% reduction in odds of metachronous neoplasia arising in the proximal colon among carriers of specific haplotypes, which was strongest (OR(proximal), 0.67; 95% CI, 0.52-0.86) for carriers of a CGGGCA haplotype (rs1805352, rs3132297, rs3132296, rs3118529, rs3118536, and rs7861779). Our results indicate that allelic variation in RXRA affects metachronous colorectal neoplasia, perhaps of particular importance in the development of proximal lesions.

    Title Sulindac and Sulindac Metabolites in Nipple Aspirate Fluid and Effect on Drug Targets in a Phase I Trial.
    Date March 2010
    Journal Cancer Prevention Research (philadelphia, Pa.)
    Excerpt

    Regular use of nonsteroidal anti-inflammatory drugs (NSAID) has been associated with reduced risk of breast cancer. Sulindac, a nonselective NSAID with both cyclooxygenase-2-dependent and -independent activities, is a candidate for breast chemoprevention. We conducted a phase Ib trial in 30 women at increased risk for breast cancer to evaluate the breast tissue distribution of sulindac at two dose levels (150 mg daily and 150 mg twice daily for 6 weeks), using nipple aspirate fluid (NAF) as a surrogate of breast tissue drug exposure. We also explored the effect of sulindac on drug-induced biomarkers in NAF. We show that sulindac and its metabolites partition to human breast as measured by NAF levels. Sulindac intervention did not decrease 13,14-dihydro-15-keto prostaglandin A(2), a stable derivative of prostaglandin E(2), in NAF, but exposure was associated with a significant trend towards higher levels of growth differentiation factor 15 in NAF in women receiving 150 mg twice daily (P = 0.038). These results are the first to show partitioning of sulindac and metabolites to human breast tissue and the first evidence for a potential dose-dependent effect of sulindac on growth differentiation factor 15 levels in NAF.

    Title Gender Modifies the Effect of Ursodeoxycholic Acid in a Randomized Controlled Trial in Colorectal Adenoma Patients.
    Date February 2010
    Journal Cancer Prevention Research (philadelphia, Pa.)
    Excerpt

    Ursodeoxycholic acid (UDCA) was one of the earliest agents investigated as a drug for colorectal cancer prevention. However, UDCA failed to show efficacy to prevent the development of colorectal adenomas in a large, phase III, randomized, placebo-controlled trial. We re-evaluated the effect of UDCA in men and women separately, based on sex-specific differences in bile acid metabolism and suspected variation in etiologic factors contributing to colorectal cancer risk.

    Title Plasma and Cerebrospinal Fluid Pharmacokinetics of Abt-888 After Oral Administration in Non-human Primates.
    Date January 2010
    Journal Cancer Chemotherapy and Pharmacology
    Excerpt

    ABT-888 inhibits poly(ADP-ribose) polymerase (PARP) and may enhance the efficacy of chemotherapy and radiation in CNS tumors. We studied the plasma and cerebrospinal fluid (CSF) pharmacokinetics (PK) of ABT-888 in a non-human primate (NHP) model that is highly predictive of human CSF penetration.

    Title Discovery of Tricyclic 5,6-dihydro-1h-pyridin-2-ones As Novel, Potent, and Orally Bioavailable Inhibitors of Hcv Ns5b Polymerase.
    Date January 2010
    Journal Bioorganic & Medicinal Chemistry Letters
    Excerpt

    A novel series of non-nucleoside small molecules containing a tricyclic dihydropyridinone structural motif was identified as potent HCV NS5B polymerase inhibitors. Driven by structure-based design and building on our previous efforts in related series of molecules, we undertook extensive SAR studies, in which we identified a number of metabolically stable and very potent compounds in genotype 1a and 1b replicon assays. This work culminated in the discovery of several inhibitors, which combined potent in vitro antiviral activity against both 1a and 1b genotypes, metabolic stability, good oral bioavailability, and high C(12) (PO)/EC(50) ratios.

    Title Physical Activity As a Determinant of Fecal Bile Acid Levels.
    Date June 2009
    Journal Cancer Epidemiology, Biomarkers & Prevention : a Publication of the American Association for Cancer Research, Cosponsored by the American Society of Preventive Oncology
    Excerpt

    Physical activity is protective against colon cancer, whereas colonic bile acid exposure is a suspected risk factor. Although likely related, the association between physical activity and bile acid levels has not been well-studied. Furthermore, the effect of triglycerides, which are known to modify bile acid levels, on this relationship has not been investigated. We conducted a cross-sectional analysis of baseline fecal bile acid levels for 735 colorectal adenoma formers obtained from participants in a phase III ursodeoxycholic acid chemoprevention trial. Compared with the lowest quartile of recreational physical activity duration, the highest quartile was associated with a 17% lower fecal bile acid concentration, adjusted for age, sex, dietary fiber intake, and body mass index (P = 0.042). Furthermore, consistent with a previously established relationship between serum triglyceride levels and bile acid metabolism, we stratified by triglyceride level and observed a 34% lower fecal bile acid concentration (highest versus lowest quartiles of physical activity) in individuals with low triglycerides (<136 mg/dL; P = 0.002). In contrast, no association between physical activity and fecal bile acid concentration was observed for subjects with high triglycerides (> or =136 mg/dL). Our results suggest that the biological mechanism responsible for the protective effect of physical activity on the incidence of colon cancer may be partially mediated by decreasing colonic bile acid exposure. However, this effect may be limited to individuals with lower triglyceride levels.

    Title Chief Nursing Officer Turnover and the Crisis Brewing: Views from the Front Line.
    Date June 2009
    Journal The Journal of Nursing Administration
    Excerpt

    This American Organization of Nurse Executives study examined perceptions of staff nurses, nurse managers, and nurses in other organizational roles as part of an initiative examining CNO turnover. Here, we report findings that complete the 3-phased effort to better understand how nurse executive turnover affects the work environment and patient care.

    Title Components of Metabolic Syndrome and Metachronous Colorectal Neoplasia.
    Date June 2009
    Journal Cancer Epidemiology, Biomarkers & Prevention : a Publication of the American Association for Cancer Research, Cosponsored by the American Society of Preventive Oncology
    Excerpt

    The consistent association between obesity and colorectal cancer is thought to be explained by metabolic disturbances common, but not exclusive, to the obese.

    Title Selective Inhibition of Pfmrk, a Plasmodium Falciparum Cdk, by Antimalarial 1,3-diaryl-2-propenones.
    Date June 2009
    Journal Bioorganic & Medicinal Chemistry Letters
    Excerpt

    The cyclin dependent protein kinases, Pfmrk and PfPK5, most likely play an essential role in cell cycle control and differentiation in Plasmodium falciparum and are thus an attractive target for antimalarial drug development. Various 1,3-diaryl-2-propenones (chalcone derivatives) which selectivity inhibit Pfmrk in the low micromolar range (over PfPK5) are identified. Molecular modeling shows a pair of amino acid residues within the Pfmrk active site which appear to confer this selectivity. Predicted interactions between the chalcones and Pfmrk correlate well with observed potency. Pfmrk inhibition and activity against the parasite in vitro correlate weakly. Several mechanisms of action have been suggested for chalcone derivatives and our study suggests that kinase inhibition may be an additional mechanism of antimalarial activity for this class of compounds.

    Title Cd20-directed Small Modular Immunopharmaceutical, Tru-015, Depletes Normal and Malignant B Cells.
    Date June 2009
    Journal Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
    Excerpt

    CD20-directed therapy with rituximab is effective in many patients with malignant lymphoma or follicular lymphoma. However, relapse frequently occurs within 1 year, and patients become increasingly refractory to retreatment. Our purpose was to produce a compact, single-chain CD20-targeting immunotherapeutic that could offer therapeutic advantages in the treatment of B-cell lymphoma.

    Title Association Between Body Mass Index and Colorectal Neoplasia at Follow-up Colonoscopy: a Pooling Study.
    Date April 2009
    Journal American Journal of Epidemiology
    Excerpt

    A direct relation between body mass index (BMI) and risk of colorectal adenomas and cancer has been reported, but few studies have had adequate sample size for conducting stratified analyses by sex, family history, colorectal subsite, or features of metachronous lesions. Data from 8,213 participants in 7 prospective studies of metachronous colorectal adenomas were pooled to assess whether the association between BMI and metachronous neoplasia varied by these factors. A statistically significant direct association between BMI and the odds of nonadvanced adenomas (P(trend) < 0.001) was observed, while the relation for advanced adenomas was of marginal significance (P(trend) < 0.07). In sex-stratified analyses, obesity was statistically significantly associated with the odds of any metachronous lesion among men (odds ratio = 1.36, 95% confidence interval: 1.17, 1.58) but not among women (odds ratio = 1.10, 95% confidence interval: 0.89, 1.37). The associations with BMI appeared to be limited to proximal neoplasia, with statistically significant results for BMI and proximal (P(trend) < 0.001), but not distal (P(trend) < 0.85), neoplasia. Exploratory analyses indicated that BMI was significantly related to most histologic characteristics of metachronous adenomas among men but not among women. Our results provide further support for the association between BMI and metachronous colorectal adenomas, particularly among men, thereby indicating that body size may affect colorectal carcinogenesis at comparatively early stages.

    Title Chief Nursing Officer Turnover: Chief Nursing Officers and Healthcare Recruiters Tell Their Stories.
    Date December 2008
    Journal The Journal of Nursing Administration
    Excerpt

    Chief nursing officers (CNOs) develop environments in which quality patient care is delivered and nurses enjoy professional practice. Because of the growing turbulence in this vital role, the American Organization of Nurse Executives conducted a study to examine CNO turnover as described in interviews with CNOs and healthcare recruiters to inform the development of strategies to improve CNO recruitment and retention and ease transition for those who turn over. The authors present the findings from this research and describe American Organization of Nurse Executives' initiatives to address the identified needs.

    Title Population Pharmacokinetics of Imatinib Mesylate and Its Metabolite in Children and Young Adults.
    Date December 2008
    Journal Cancer Chemotherapy and Pharmacology
    Excerpt

    Imatinib mesylate (Gleevec) is a small molecule tyrosine kinase inhibitor approved for use in the management of chronic myeloid leukemia in adults and children and in gastrointestinal stromal tumors in adults. Population pharmacokinetic (PPK) studies evaluating the effect of population covariates on the pharmacokinetics of imatinib and its active metabolite have been developed in adults with chronic myeloid leukemia (CML) and gastrointestinal stromal tumor (GIST). However, this still remains to be described in children.

    Title Pharmacokinetics of Irinotecan and Its Metabolites in Pediatric Cancer Patients: a Report from the Children's Oncology Group.
    Date December 2008
    Journal Cancer Chemotherapy and Pharmacology
    Excerpt

    To develop a population pharmacokinetic model of irinotecan and its major metabolites in children with cancer and to identify covariates that predict variability in disposition.

    Title Managing Cellulitis and Impetigo.
    Date December 2008
    Journal Nursing
    Title Long-term Anti-inflammatory and Antihistamine Medication Use and Adult Glioma Risk.
    Date September 2008
    Journal Cancer Epidemiology, Biomarkers & Prevention : a Publication of the American Association for Cancer Research, Cosponsored by the American Society of Preventive Oncology
    Excerpt

    A personal history of asthma or allergy has been associated with a reduced risk for adult malignant gliomas. Recent reports on the use of nonsteroidal anti-inflammatory drugs (NSAID) and the presence of risk alleles in asthma susceptibility genes showed similar inverse associations. To further explore the relationship between immune mediators and gliomas, we examined the use of NSAID and antihistamines, history of asthma or allergy, and infection in 325 glioma cases and 600 frequency-matched controls from the metropolitan area of Houston, TX (2001-2006). The regular use of NSAID was associated with a 33% reduction in the risk for glioma, suggestive of possible antitumor activity. Surprisingly, regular long-term antihistamine use among those reporting a history of asthma or allergies was significantly associated with a 3.5-fold increase in the risk for glioma. Similar to previous reports, cases in our study were less likely to have reported asthma, allergy, or a history of a number of viral infections (chickenpox or shingles, oral herpes, and mononucleosis) than controls. We therefore speculate that the observed positive association with antihistamine use may reflect an alteration of protective immune factors in susceptible individuals. Our results lend additional support for an important but unknown link between malignant brain tumors and immune mediators.

    Title What You Should Know About Psoriasis.
    Date September 2008
    Journal Nursing
    Title When Your Patient Has Atopic Dermatitis.
    Date August 2008
    Journal Nursing
    Title Presence of a Ta Haplotype in the Apc Gene Containing the Common 1822 Polymorphism and Colorectal Adenoma.
    Date August 2008
    Journal Cancer Research
    Excerpt

    Acquired or inherited mutations in the adenomatous polyposis coli (APC) tumor suppressor gene are causally linked to colorectal cancer. Given the significance of APC in colorectal cancer, we investigated the association between common single-nucleotide polymorphisms (SNP) in the APC gene and the odds of developing metachronous colorectal adenomas as a surrogate measure of colorectal cancer risk. Coding SNPs at codons 486, 1678, 1822, 1960, and 2502 were analyzed in a total of 1,399 subjects who participated in two randomized clinical trials for the prevention of colorectal adenomas. No association was found for any single SNP and the odds of metachronous adenoma. In contrast, a TA haplotype (codons 486 and 1822) was associated with a statistically significant 27% and 26% reduction in the odds of any and nonadvanced metachronous adenoma after adjustment for baseline adenoma characteristics [odds ratio (OR), 0.73; 95% confidence interval (95% CI), 0.59-0.91 and OR, 0.74; 95% CI, 0.57-0.94], respectively. No significant reduction in odds was observed for advanced metachronous lesions. Diplotype analysis revealed a strong gene dose effect with carriers of two alleles containing TT-AA (codons 486 and 1822, respectively) having an 89% lower odds for advanced metachronous adenomas (OR, 0.11; 95% CI, 0.01-0.80) when compared with the common CC-AA diplotype (codons 486 and 1822, respectively). Our findings support an important role for germ-line allele sequence in the APC gene and individual risk of metachronous adenomatous polyps.

    Title Chief Nursing Officer Retention and Turnover: a Crisis Brewing? Results of a National Survey.
    Date July 2008
    Journal Journal of Healthcare Management / American College of Healthcare Executives
    Excerpt

    Anecdotal evidence suggests growing concerns about chief nursing officer (CNO) dissatisfaction, intent to leave, and turnover. However, little evidence documents the magnitude of the problem or whether CNO turnover requires direct action. This article reports the results from the first phase of a three-phase study examining CNO turnover and retention in U.S. hospitals. CNOs were invited to complete an online survey to gather data about their experiences with turnover and to identify CNO retention issues. Our sample includes responses from 622 CNOs employed in hospitals and healthcare systems across the United States. Approximately 38 percent of the respondents reported having left a CNO position-13 percent within two years before the survey and 25 percent within five years before the survey. Of these, approximately one-quarter had been asked to resign, had been terminated, or had lost their jobs involuntarily. When asked about the context of their departure, a high percentage reported leaving their position to pursue another CNO position (50 percent) or for career advancement (30 percent); approximately 26 percent reported leaving because of conflicts with the chief executive officer. Of great concern is the finding that approximately 62 percent of respondents anticipate making a job change in less than five years, slightly more than one-quarter for retirement. Respondents clearly indicated that CNO turnover is a problem that requires attention. The knowledge gained from this study can be used by healthcare leaders to develop strategies and policies aimed at recruiting and retaining CNOs and easing the transition for CNOs and others in the organization when CNO turnover does

    Title Structure of Hepatitis C Virus Ires Subdomain Iia.
    Date July 2008
    Journal Acta Crystallographica. Section D, Biological Crystallography
    Excerpt

    The hepatitis C (HCV) internal ribosome entry site (IRES) element plays a central role in cap-independent translation of the viral genomic RNA. The unique conformation of IRES domain II is critical for 80S ribosomal assembly and initiation of viral translation. Here, the crystal structure of subdomain IIa of the HCV IRES has been determined at 2.3 A resolution, revealing the positions of divalent metal ions and complex inter-strand interactions that stabilize the L-shaped conformation of the RNA. The presence of divalent metal ions was necessary for crystal formation. Magnesium ions occupy specific sites that appear to be critical for the formation of the folded conformation. Subdomain IIa also was crystallized in the presence of strontium, which improved the diffraction quality of the crystals and the ability to identify interactions of the RNA with metal ions and tightly bound water molecules. The hinge region and noncanonical G-U base-pair motifs are stabilized by divalent metal ions and provide unique structural features that are potential interaction sites for small-molecule ligands. The information obtained from the crystal structure provides a basis for structure-guided design of HCV translation inhibitors targeting disruption of ribosomal assembly.

    Title Assessing Skin Rashes.
    Date May 2008
    Journal Nursing
    Title Plasma Insulin-like Growth Factor I is Inversely Associated with Colorectal Adenoma Recurrence: a Novel Hypothesis.
    Date May 2008
    Journal Cancer Epidemiology, Biomarkers & Prevention : a Publication of the American Association for Cancer Research, Cosponsored by the American Society of Preventive Oncology
    Excerpt

    The insulin-like growth factor I (IGF-I) axis has been proposed to be a significant factor in the development of certain cancers, including colorectal. However, results from epidemiologic studies suggest modest effects on colorectal cancer risk. Using cross-sectional and prospective study designs within the same cohort of men who had at least one adenoma at baseline, we investigated whether plasma IGF-I, IGF-I binding protein 1, and IGF-I binding protein 3 were associated with colorectal adenoma characteristics at baseline and whether their levels were related to odds for adenoma recurrence. Plasma levels of each marker were measured at baseline in 299 male participants in the Wheat Bran Fiber Trial, who were followed prospectively for recurrence of their adenomatous lesions. In cross-sectional analyses, plasma IGF-I was significantly positively associated with the presence of adenomas with any villous features (P = 0.04). In contrast, IGF-I levels were inversely associated with odds of colorectal adenoma recurrence, with adjusted odds ratios (95% confidence interval) of 0.55 (0.29-1.01) and 0.49 (0.26-0.91) for the second and third tertiles of IGF-I, respectively, compared with the first tertile (P(trend) = 0.02). The inverse association was stronger for advanced adenoma recurrence (P(trend) = 0.02) than for nonadvanced recurrence (P(trend) = 0.10). These results suggest that, once an adenoma is removed, higher IGF-I levels reduce the odds of the formation of new lesions in the colorectum.

    Title Plasma and Cerebrospinal Fluid Pharmacokinetics of Valproic Acid After Oral Administration in Non-human Primates.
    Date April 2008
    Journal Cancer Chemotherapy and Pharmacology
    Excerpt

    PURPOSE: Valproic acid (VPA), a widely used antiepileptic, also inhibits histone deacetylase (HDAC), and is undergoing evaluation as an anti-cancer agent. We studied the pharmacokinetics of VPA in the plasma and cerebrospinal fluid (CSF) in a non-human primate model that is highly predictive of human CSF penetration to determine if levels of VPA required to inhibit HDAC in in vivo models can be attained. METHODS: Oral VPA, 75 mg/kg, was administered to four non-human primates. Serial samples of blood (n = 4) and CSF (n = 3) were obtained for pharmacokinetic studies of total and free VPA. Plasma and CSF VPA concentrations were measured using the commercially available Abbott AxSYM VPA assay reagent system (Abbott Laboratories, Abbott Park, IL, USA). The resultant plasma and CSF data were evaluated using pharmacokinetic modeling methods. RESULTS: At a dose of 75 mg/kg, the maximum plasma concentration of VPA was 130.1 +/- 70.6 microg/ml (mean +/- standard deviation) for total drug and 53.3 +/- 44.4 microg/ml for free drug. The mean plasma area under the curve (AUC) for total drug was 680 +/- 233 microg/ml h and for free drug 146 +/- 89 microg/ml hr. The maximum CSF concentration occurred 2-3 h after administration and was 28.2 +/- 18.6 microg/ml. The CSF AUC for VPA was 108 +/- 52 microg/ml h. The CSF penetration of VPA was 12.9 +/- 5.1% for total drug and 57.0 +/- 8.7% for free drug. Disappearance from the plasma followed non-linear kinetics with a V (max) of 321.2 +/- 65.6 microg/kg/min and a K (m) of 17.2 +/- 13.7 mg/l. CONCLUSION: Valproic acid deserves further study for the treatment of CNS tumors given its high CSF penetration after oral dosing coupled with the anti-tumor activity observed in preclinical studies.

    Title Retention of Upper Limb Function in Stroke Survivors Who Have Received Constraint-induced Movement Therapy: the Excite Randomised Trial.
    Date March 2008
    Journal Lancet Neurology
    Excerpt

    BACKGROUND: The aim of constraint-induced movement therapy (CIMT) is to promote use of a limb that is functionally impaired after a stroke. In one form of CIMT to treat upper limb impairment, use of the less severely affected arm is restricted for many hours each weekday over 2 consecutive weeks. The EXCITE trial has previously shown the efficacy of this intervention for patients 3-9 months poststroke who were followed-up for the next 12 months. We assessed the retention of improvements 24 months after the intervention. METHODS: In the EXCITE trial, 106 of 222 participants who had mild to moderate poststroke impairments were randomly assigned to receive CIMT rather than usual and customary care. We assessed this group of patients every 4 months for the primary outcome measure of impaired upper limb function, as measured with the Wolf motor function test (WMFT) and the motor activity log (MAL). Health-related quality of life, measured with the stroke impact scale (SIS), was a secondary outcome measure. Analysis was per protocol. This trial is registered with ClinicalTrials.gov, number NCT00057018. FINDINGS: The effects at 24 months after treatment did not decline from those at 12 months for time taken to complete the WMFT (-0.32 s, 95% CI -3.70 to 3.06), for weight lifted in the WMFT (-1.39 kg, -2.74 to -0.04), for WMFT grip strength (-4.39 kg, -6.91 to -1.86), for amount of use in the MAL (-0.17, -0.38 to 0.04), or for how well the limb was used in the MAL (-0.14, -0.34 to 0.06). The additional changes were in the direction of increased therapeutic effect. For the strength components of the WMFT, p<0.0001. INTERPRETATION: Patients who have mild to moderate impairments 3-9 months poststroke have substantial improvement in functional use of the paretic upper limb and quality of life 2 years after a 2-week CIMT intervention. Thus, this intervention has persistent benefits.

    Title Malaria Incidence and Efficacy of Intermittent Preventive Treatment in Infants (ipti).
    Date March 2008
    Journal Malaria Journal
    Excerpt

    Intermittent preventive antimalarial treatment in infants (IPTi) is currently evaluated as a malaria control strategy. Among the factors influencing the extent of protection that is provided by IPTi are the transmission intensity, seasonality, drug resistance patterns, and the schedule of IPTi administrations. The aim of this study was to determine how far the protective efficacy of IPTi depends on spatio-temporal variations of the prevailing incidence of malaria.

    Title Meat Intake, Preparation Methods, Mutagens and Colorectal Adenoma Recurrence.
    Date March 2008
    Journal Carcinogenesis
    Excerpt

    Red meat intake has been shown to be associated with higher risk of colorectal cancer. Though the exact mechanisms responsible for this association remain unknown, several tumorigenic properties of meat have been proposed. One well-supported biologic mechanism is elevated exposure to the genotoxic formation of heterocyclic amines (HCAs), which occur when meat is cooked at high temperatures for a long period of time. We prospectively assessed the relation between type of meat, meat preparation method, doneness, a metric of HCAs and other mutagens and colorectal adenoma recurrence among 869 participants in a chemoprevention trial of ursodeoxycholic acid. Unconditional logistic regression analyses were used to estimate odds ratios (ORs) and associated 95% confidence intervals (CIs). Most meat variables assessed were positively but weakly associated with recurrence of any adenoma. In contrast, recurrence of advanced or multiple adenomas was more strongly associated with a number of the meat exposure variables evaluated. For recurrence of advanced lesions, significant associations were detected among individuals in the highest when compared with the lowest tertile of intake for pan-fried red meat (OR = 1.85; 95% CI = 1.10-3.13) and well/very well done red meat (OR = 1.71; 95% CI = 1.02-2.86). Significant positive associations were shown for recurrence of multiple adenomas and the following variables: processed meat (OR = 1.83; 95% CI = 1.10-3.04), pan-fried red meat (OR = 1.63; 95% CI = 1.01-2.61), well/very well done red meat (OR = 1.68; 95% CI = 1.03-2.74), 2-amino-3,4,8-trimethylimidazo[4,5,-f]quinoxaline (OR = 1.74; 95% CI = 1.07-2.82) and 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (OR = 1.68; 95% CI = 1.03-2.75). Our results support a meat mutagen exposure hypothesis as a potential mechanism for recurrence of clinically significant adenomatous polyps.

    Title Immunonanoshells for Targeted Photothermal Ablation in Medulloblastoma and Glioma: an in Vitro Evaluation Using Human Cell Lines.
    Date February 2008
    Journal Journal of Neuro-oncology
    Excerpt

    We are developing a novel approach to specifically target malignant brain tumor cells for photothermal ablation using antibody-tagged, near infrared-absorbing gold-silica nanoshells, referred to as immunonanoshells. Once localized to tumor cells, these nanoshells are extremely efficient at absorbing near-infrared light and can generate sufficient heat to kill cancer cells upon exposure to laser light. In this study, we evaluated the efficacy of immunonanoshells in vitro against both medulloblastoma and high-grade glioma cell lines. We used an antibody against HER2 to target gold-silica nanoshells to medulloblastoma cells, since HER2 is frequently overexpressed in medulloblastoma. We show that treatment with HER2-targeted nanoshells, but not non-targeted nanoshells, followed by exposure to laser light, can induce cell death in the HER2-overexpressing medulloblastoma cell line Daoy.2, as well as the parental Daoy cell line, which expresses HER2 at a moderate level, but not in dermal fibroblasts that do not express HER2. In an analogous set of experiments, we conjugated gold-silica nanoshells to an antibody against interleukin-13 receptor-alpha 2 (IL13Ralpha2), an antigen that is frequently overexpressed in gliomas. We demonstrate that these immunonanoshells are capable of inducing cell death in two high-grade glioma cell lines that express IL13Ralpha2, U373 and U87, but not in A431 epidermoid carcinoma cells that do not express significant levels of IL13Ralpha2. We believe that the use of antibody-tagged gold-silica nanoshells to selectively target cancer cells presents a promising new strategy for the treatment of central nervous system tumors that will minimize the damage and resulting toxicity to the surrounding normal brain.

    Title Diet, Gender, and Colorectal Neoplasia.
    Date December 2007
    Journal Journal of Clinical Gastroenterology
    Excerpt

    The association between diet and colorectal cancer has been studied in depth for many decades, with equivocal results. It has been hypothesized that cancers arising in the distal and proximal colon have different pathologies, and therefore different risk factors. As such, it is possible that diet-related factors might influence colorectal neoplasia differently depending on the subsite. Recent evidence indicates that women may be more likely to develop proximal cancers than men. Additionally, the link between certain dietary factors and colorectal neoplasia in women seems to vary by menopausal status. Given these observations, women may be affected differently than men by diet-related factors. The objective of this article was therefore to review the data for diet and colorectal adenomas and cancer, and then attempt to address the potential differences in the association of diet-related factors and colorectal neoplasia in men and women. For total energy intake, selenium, and fiber, it seems that there may be slightly stronger effects in men as compared with women, whereas calcium and folate seem to affect both sexes similarly. With regard to vitamin D and colorectal cancer, women may exhibit stronger associations than men. Perhaps the most evidence for a sex-specific effect is observed for obesity, where more substantial direct relationships between body size and colorectal neoplasia have been reported for men than for women. However, this observation may be influenced by the differential effects in women by menopausal status. Further research on sex-specific dietary effects is warranted.

    Title Association Between Body Size and Colorectal Adenoma Recurrence.
    Date November 2007
    Journal Clinical Gastroenterology and Hepatology : the Official Clinical Practice Journal of the American Gastroenterological Association
    Excerpt

    BACKGROUND & AIMS: Obesity has been associated with increased risk for colorectal adenoma, although its role as a risk factor after polypectomy for recurrence is unclear. Therefore, we sought to evaluate the effect of anthropometric measures of obesity on adenoma after polypectomy. METHODS: Subjects with baseline adenomas (n = 2465) and follow-up colonoscopy data were drawn from 2 randomized trials designed to prevent adenoma recurrence. RESULTS: Over a mean follow-up period of 3.1 years presence of a body mass index (BMI) > or = 30 kg/m2 was associated with a nonsignificant 17% increase in the odds for any adenoma recurrence among all subjects (odds ratio [OR], 1.17; 95% confidence interval [CI], 0.92-1.48). This result was confined to men (OR, 1.36; 95% CI, 1.01-1.83) and not observed for women (OR, 0.90; 95% CI, 0.60-1.33). Results for waist circumference did not reach statistical significance, although trends were similar to those for BMI. Analyses of the effects of obesity on more clinically significant lesions demonstrated that high BMI was a slightly stronger risk factor for advanced adenoma recurrences in men (OR, 1.62; 95% CI, 1.04-2.53) when compared with non-advanced lesions (OR, 1.26; 95% CI, 0.91-1.75). In addition, we observed an association for obesity and odds of adenoma recurrence among participants reporting a family history of colorectal cancer (OR, 2.25; 95% CI, 1.32-3.84) but not for those without (OR, 1.00; 95% CI, 0.77 to 1.31; P(int) = P = .008). CONCLUSIONS: Our results support obesity as a risk factor for subsequent short-interval (mean follow-up time 3.1 years) development of colorectal adenomas, particularly among men and persons with a family history of colorectal cancer. Furthermore, obesity in men appears to be strongly associated with the development of clinically advanced lesions.

    Title Phase I Pharmacokinetic and Pharmacodynamic Study of Temozolomide in Pediatric Patients with Refractory or Recurrent Leukemia: a Children's Oncology Group Study.
    Date November 2007
    Journal Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
    Excerpt

    PURPOSE: To determine the tolerability, pharmacokinetics, and mechanisms of temozolomide resistance in children with relapsed or refractory leukemia. PATIENTS AND METHODS: Cohorts of three to six patients received 200 or 260 mg/m2/d of temozolomide by mouth daily for 5 days every 28 days. Toxicities, clinical response, and pharmacokinetics were evaluated. Pretreatment leukemia cell O6-methylguanine-DNA methyltransferase (MGMT) activity, tumor and plasma MGMT promoter methylation, and microsatellite instability (MSI) were examined in 14 of 16 study patients and in tissue bank samples from children with acute leukemia not treated with temozolomide (MGMT, n = 67; MSI, n = 65). RESULTS: Sixteen patients (nine female, seven male; acute lymphoblastic leukemia [ALL], n = 8; acute myeloid leukemia [AML], n = 8), median age 11 years (range, 1 to 19 years), received either 200 mg/m2/d (nine enrolled, three assessable for toxicity) or 260 mg/m2/d (seven enrolled, three assessable for toxicity) of temozolomide. Temozolomide was well tolerated and no dose-limiting toxicities occurred. The mean clearance of temozolomide was 107 mL/min/m2, with a volume of distribution of 20 L/m2 and half-life of 109 minutes. MGMT activity in leukemia cells was quite variable and was highest in patients with relapsed ALL. Only one patient had MSI. Two patients had a partial response. Both of these patients had no detectable MGMT activity; both also had methylated MGMT promoters and were MSI stable. CONCLUSION: Temozolomide was well tolerated at doses as high as 260 mg/m2/d for 5 days in children with relapsed or refractory leukemia. Increased MGMT activity may account for the temozolomide resistance in children with relapsed leukemia. Leukemia cell MGMT activity was higher in pediatric ALL than AML (P < .0001).

    Title Comprehensive Molecular Diagnostics in Autosomal Dominant Polycystic Kidney Disease.
    Date October 2007
    Journal Journal of the American Society of Nephrology : Jasn
    Excerpt

    Mutation-based molecular diagnostics of autosomal dominant polycystic kidney disease (ADPKD) is complicated by genetic and allelic heterogeneity, large multi-exon genes, duplication of PKD1, and a high level of unclassified variants (UCV). Present mutation detection levels are 60 to 70%, and PKD1 and PKD2 UCV have not been systematically classified. This study analyzed the uniquely characterized Consortium for Radiologic Imaging Study of PKD (CRISP) ADPKD population by molecular analysis. A cohort of 202 probands was screened by denaturing HPLC, followed by direct sequencing using a clinical test of 121 with no definite mutation (plus controls). A subset was also screened for larger deletions, and reverse transcription-PCR was used to test abnormal splicing. Definite mutations were identified in 127 (62.9%) probands, and all UCV were assessed for their potential pathogenicity. The Grantham Matrix Score was used to score the significance of the substitution and the conservation of the residue in orthologs and defined domains. The likelihood for aberrant splicing and contextual information about the UCV within the patient (including segregation analysis) was used in combination to define a variant score. From this analysis, 44 missense plus two atypical splicing and seven small in-frame changes were defined as probably pathogenic and assigned to a mutation group. Mutations were thus defined in 180 (89.1%) probands: 153 (85.0%) PKD1 and 27 (15.0%) PKD2. The majority were unique to a single family, but recurrent mutations accounted for 30.0% of the total. A total of 190 polymorphic variants were identified in PKD1 (average of 10.1 per patient) and eight in PKD2. Although nondefinite mutation data must be treated with care in the clinical setting, this study shows the potential for molecular diagnostics in ADPKD that is likely to become increasingly important as therapies become available.

    Title Relationship Between Epidemiologic Risk Factors and Breast Cancer Recurrence.
    Date October 2007
    Journal Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
    Excerpt

    PURPOSE: Early-stage breast cancers are biologically heterogeneous and vary in clinical behavior, supporting the role of factors other than tumor size and lymph node involvement as outcome determinants. We evaluated the effect of epidemiologic breast cancer risk factors on recurrence in women with early-stage disease. PATIENTS AND METHODS: Medical records from 2,327 women with early-stage breast cancer, treated at the M.D. Anderson Cancer Center between 1985 and 2000, were used to derive information on epidemiologic, clinical, and histological factors. Cox proportional hazards models were used to estimate the hazard ratios of 5-year risk of breast cancer recurrence adjusted for treatment and stage. Statistical tests were two-sided. RESULTS: None of the breast cancer risk factors were associated with recurrence, adjusting for tumor characteristics and treatment. A significant interaction between hormone replacement therapy (HRT) use and tumor hormone receptor status on risk of recurrence (P = .0003) was observed. Among ever-users of HRT, recurrence risk was two-fold lower for estrogen receptor (ER)--positive and progesterone receptor (PR)--positive tumors compared with ER- and PR-negative tumors; whereas, among never-users of HRT, there was no statistically significant association between recurrence risk and receptor status. CONCLUSION: HRT users who develop receptor-positive early-stage disease have better outcomes than those who develop receptor-negative disease. Among never-users of HRT, the expected beneficial effect of ER- or PR-positive tumors on recurrence risk was absent. These data lend support to the notion that the biology of hormone receptor-positive disease in HRT users differs from that in nonusers.

    Title Magnetic Resonance Measurements of Renal Blood Flow and Disease Progression in Autosomal Dominant Polycystic Kidney Disease.
    Date September 2007
    Journal Clinical Journal of the American Society of Nephrology : Cjasn
    Excerpt

    Whether changes in renal blood flow (RBF) are associated with and possibly contribute to cystic disease progression in autosomal dominant polycystic kidney disease (ADPKD) has not been ascertained. The Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease (CRISP) was created to develop imaging techniques and analyses to evaluate progression. A total of 131 participants with early ADPKD had measurements of RBF and total kidney (TKV) and cyst (TCV) volumes by magnetic resonance and of GFR by iothalamate clearance at baseline and 1, 2, and 3 yr. The effects of age, gender, body mass index, hypertension status, mean arterial pressure (MAP), TKV, TCV, RBF, renal vascular resistance (RVR), GFR, serum uric acid, HDL and LDL cholesterol, 24-h urine volume, sodium (UNaE) and albumin (UAE) excretions, and estimated protein intake were examined at baseline on TKV, TCV, and GFR slopes. TKV and TCV increased, RBF decreased, and GFR remained stable. TKV, TCV, RVR, serum uric acid, UAE, UNaE, age, body mass index, MAP, and estimated protein intake were positively and RBF and GFR negatively correlated with TKV and TCV slopes. TKV, RBF, UNaE, and UAE were independent predictors of TKV and TCV slopes (structural disease progression). TKV, TCV, RVR, and MAP were negatively and RBF positively correlated with GFR slopes. Regression to the mean confounded the analysis of GFR slopes. TKV and RBF were independent predictors of GFR decline (functional disease progression). In ADPKD, RBF reduction (1) parallels TKV increase, (2) precedes GFR decline, and (3) predicts structural and functional disease progression.

    Title Abnormalities of Cingulate Gyrus Neuroanatomy in Schizophrenia.
    Date August 2007
    Journal Schizophrenia Research
    Excerpt

    OBJECTIVE AND METHODS: Abnormalities of the neuroanatomy of the gray matter of the cingulate gyrus, especially its anterior segment, have been suggested to be an important characteristic of schizophrenia. In this study, T1-weighted magnetic resonance scans were collected in 53 individuals with schizophrenia and 68 comparison subjects matched for age, gender, race and parental socioeconomic status. We applied Labeled Cortical Mantle Distance Mapping to assess the volume, surface area and thickness of the cortical mantle within the anterior (AC) and posterior (PC) segments of the cingulate gyrus, excluding the paracingulate gyrus, and related these anatomical measures to measures of psychopathology and illness duration. RESULTS: After covarying for total cerebral volume, individuals with schizophrenia showed smaller AC gray matter volume (p=0.024), thickness (trend, p=0.081), but not surface area (p=0.16), than comparison subjects. Similar group differences were found for PC gray matter volume (p=0.0005) and thickness (trend, p=0.055), but not surface area (p=0.15). Across both groups, there was a significant L>R asymmetry in thickness of the AC, and a significant L>R asymmetry in the surface area of the PC. However, there were no significant group-by-hemisphere interactions. In the individuals with schizophrenia, thinning of the AC, but not the PC, was correlated with a longer duration of illness and a greater severity of psychotic symptoms. CONCLUSIONS: Individuals with schizophrenia showed smaller gray matter volumes across the entire cingulate gyrus, mostly due to a reduction in cortical mantle thickness. However, structural measures of the AC were more closely related to clinical features of the illness.

    Title Magnetic Resonance Imaging Evaluation of Hepatic Cysts in Early Autosomal-dominant Polycystic Kidney Disease: the Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease Cohort.
    Date August 2007
    Journal Clinical Journal of the American Society of Nephrology : Cjasn
    Excerpt

    The objective of this study was to investigate the prevalence of hepatic cysts by age and gender in patients with early autosomal-dominant polycystic kidney disease (ADPKD) and to determine whether hepatic cyst volume is related to renal and renal cyst volumes by using magnetic resonance imaging (MRI). A total of 230 patients with ADPKD (94 men and 136 women) who were aged 15 to 46 yr and had relatively preserved renal function were studied. MRI images of the kidney and liver were obtained to measure renal, renal cyst, and hepatic cyst volumes. These volume measurements and hepatic cyst prevalence were compared in all patients and in subgroups on the basis of gender and age (15 to 24, 25 to 34, and 35 to 46 yr). The overall prevalence of hepatic cysts was 83%; the prevalence was 58, 85, and 94% in the sequential age groups and 85% in women and 79% in men. The prevalence was related directly to renal volume (chi2 = 4.30, P = 0.04) and to renal cyst volume (chi2 = 5.59, P = 0.02). The total hepatic cyst volume was significantly greater in women than in men (a logarithmic transformation mean of 5.27 versus 1.94 ml; P = 0.003). The average hepatic cyst volume was 0.25, 5.75, and 22.78 ml in sequential age groups. Hepatic cysts are evident in 94% of patients who are older than 35 yr and in 55% of individuals who are younger than 25 yr. Hepatic cysts are more prevalent and larger in total cyst volume in women than in men. Hepatic cyst prevalence and aggregate total hepatic cyst volume increased with age.

    Title A Randomized Controlled Trial of Extended Intermittent Preventive Antimalarial Treatment in Infants.
    Date July 2007
    Journal Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America
    Excerpt

    Intermittent preventive antimalarial treatment in infants (IPTi) with sulfadoxine-pyrimethamine reduces falciparum malaria and anemia but has not been evaluated in areas with intense perennial malaria transmission. It is unknown whether an additional treatment in the second year of life prolongs protection.

    Title Cyst Number but Not the Rate of Cystic Growth is Associated with the Mutated Gene in Autosomal Dominant Polycystic Kidney Disease.
    Date June 2007
    Journal Journal of the American Society of Nephrology : Jasn
    Excerpt

    Data from serial renal magnetic resonance imaging of the Consortium of Radiologic Imaging Study of PKD (CRISP) autosomal dominant polycystic kidney disease (PKD) population showed that cystic expansion occurs at a consistent rate per individual, although it is heterogeneous in the population, and that larger kidneys are associated with more rapid disease progression. The significance of gene type to disease progression is analyzed in this study of the CRISP cohort. Gene type was determined in 183 families (219 cases); 156 (85.2%) had PKD1, and 27 (14.8%) had PKD2. PKD1 kidneys were significantly larger, but the rate of cystic growth (PKD1 5.68%/yr; PKD2 4.82%/yr) was not different (P = 0.24). Cyst number increased with age, and more cysts were detected in PKD1 kidneys (P < 0.0001). PKD1 is more severe because more cysts develop earlier, not because they grow faster, implicating the disease gene in cyst initiation but not expansion. These insights will inform the development of targeted therapies in autosomal dominant PKD.

    Title Methotrexate Pharmacokinetics in Infants with Acute Lymphoblastic Leukemia.
    Date May 2007
    Journal Cancer Chemotherapy and Pharmacology
    Excerpt

    PURPOSE: We performed a pharmacokinetic evaluation of methotrexate (MTX) in infants with acute lymphoblastic leukemia enrolled on the Pediatric Oncology Group (POG) 9407 Infant Leukemia Study to evaluate the effects of age on MTX pharmacokinetics and pharmacodynamics. METHODS: A pharmacokinetic database of 61 patients was developed by combining MTX data obtained from 16 patients in a pharmacokinetic sub-study with data obtained for clinical care in other patients enrolled on the POG 9407 protocol. The data were analyzed for the first dose of MTX given to patients in induction/intensification therapy. Patients received MTX (4 g/m2) over 24 h at week 4 of therapy. Toxicity data were also reviewed to evaluate the incidence of common MTX toxicities during the first 6 weeks of therapy (the induction/intensification phase). RESULTS: Steady-state clearance (mean+/-standard deviation) for infants aged 0-6 months was 89+/-32 ml/min/m2 compared to 111+/-40 for infants aged 7-12 months (P=0.030). In the subgroup of infants aged 0-3 months the mean steady-state clearance was 84+/-30 ml/min/m2 (P=0.026 vs. the 7-12-month group). The incidence of renal toxicity (all grades) during induction/intensification therapy was 23% in the 0-3 months age group compared to 0% (for n=27) in the group 7-12 months of age (P=0.029). There were no significant differences in hepatoxicity or mucous membrane toxicity between age groups. CONCLUSIONS: A modest difference in steady-state MTX clearance is observed between younger infants (0-6 months) and older infants (7-12 months). Very young infants (0-3 months) also experienced a slightly higher incidence of renal toxicity during induction/intensification therapy. Steady-state clearance for the older infants is similar to values reported for children in other studies.

    Title Serum 25(oh)d Levels, Dietary Intake of Vitamin D, and Colorectal Adenoma Recurrence.
    Date May 2007
    Journal The Journal of Steroid Biochemistry and Molecular Biology
    Excerpt

    There is strong epidemiological and laboratory evidence that vitamin D may be protective against colorectal neoplasia. Therefore, we sought to assess the relationship between serum 25(OH)D levels, dietary intake of vitamin D, and colorectal adenoma recurrence in our ursodeoxycholic acid trial. A total of 568 participants were randomly selected for analysis of serum 25(OH)D levels. The range of total 25(OH)D was 5.5-66.1 ng/ml, with a median of 25.6 ng/ml. After categorizing 25(OH)D levels into tertiles based on the population distribution, the adjusted odds ratios (95% CI) for adenoma recurrence in the second and third tertiles were 0.88 (0.56-1.39) and 0.78 (0.49-1.24), respectively. The association between serum 25(OH)D and adenoma recurrence appeared to be stronger among women than men. As compared to those below the median value, women with serum 25(OH)D levels above the median had an OR (95% CI) of 0.59 (0.30-1.16); the corresponding OR (95% CI) for men was 0.95 (0.60-1.49). Analyses by dietary vitamin D intake revealed no statistically significant associations. In summary, the results of this study show a moderate, nonsignificant inverse association between serum 25(OH)D levels and reduced risk for colorectal adenoma recurrence, particularly among women.

    Title A Phase 1 Study of the Proteasome Inhibitor Bortezomib in Pediatric Patients with Refractory Leukemia: a Children's Oncology Group Study.
    Date May 2007
    Journal Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
    Excerpt

    PURPOSE: A phase 1 study to determine the maximum-tolerated dose, dose-limiting toxicity, pharmacokinetics, and biological effects of bortezomib in children with recurrent/refractory leukemia. EXPERIMENTAL DESIGN: Bortezomib was administered twice weekly for 2 consecutive weeks at either 1.3 or 1.7 mg/m(2) dose followed by a 1-week rest. Bortezomib pharmacokinetics and nuclear factor kappaB (NF-kappaB) binding activity were evaluated during the first treatment cycle. RESULTS: Twelve patients (nine with acute lymphoblastic leukemia, three with acute myelogenous leukemia), median age 11 years (range, 1-18 years), were enrolled between May 2004 and November 2005, of whom seven were not fully evaluable for toxicity due to rapidly progressive disease or uncontrolled infection. Dose-limiting toxicities occurred in two patients at the 1.7 mg/m(2) dose level. One patient experienced grade 3 confusion and the other patient had grade 4 febrile neutropenia associated with grade 4 hypotension and grade 3 creatinine. Pharmacokinetic analysis at 1.3 mg/m(2) revealed a clearance of 11 mL/h/m(2), a central volume of distribution of 6.7 L/m(2), and a terminal half-life of 12.6 h. NF-kappaB activity was examined in five patients and was noted to transiently increase and then decrease 4- to 6-fold by 24 h following bortezomib in two patients. There were no objective clinical responses. CONCLUSIONS: For children with leukemia, the recommended phase 2 dose of bortezomib, administered twice weekly for 2 weeks followed by a 1-week rest, is 1.3 mg/m(2)/dose. Although bortezomib treatment inhibited NF-kappaB activity, bortezomib had little activity as a single agent in this population.

    Title Back and Pelvic Pain in an Underserved United States Pregnant Population: a Preliminary Descriptive Survey.
    Date April 2007
    Journal Journal of Manipulative and Physiological Therapeutics
    Excerpt

    OBJECTIVE: The objective of this study was to identify the prevalence of back pain and treatment satisfaction in a population of low-socioeconomic pregnant women. METHODS: This study used a cross-sectional design to determine the prevalence of self-reported musculoskeletal pain in pregnancy for 599 women. Women completed an author-generated musculoskeletal survey in the second trimester of their pregnancy that addressed pain history, duration, location, and intensity, as well as activities of daily living, treatment frequency, and satisfaction with treatment. RESULTS: Sixty-seven percent of the total population reported musculoskeletal pain, and nearly half presented with a multi-focal pattern of pain that involved 2 or more sites. Twenty-one percent reported severe pain intensity rated on a numerical rating scale. Eighty percent of women experiencing pain slept less than 4 hours per night and 75% of these women took pain medications. Importantly, 85% of the women surveyed perceived that they had not been offered treatment for their musculoskeletal disorders. CONCLUSION: Multi-focal musculoskeletal pain in pregnancy was prevalent in this underserved patient population. The pain in this population negatively affected sleep and treatment appeared inadequate.

    Title Plasma and Cerebrospinal Fluid Pharmacokinetics of Pemetrexed After Intravenous Administration in Non-human Primates.
    Date March 2007
    Journal Cancer Chemotherapy and Pharmacology
    Excerpt

    PURPOSE: Pemetrexed, a multi-targeted antifolate that disrupts synthesis of both purines and pyrimidines, is approved for use in malignant pleural mesothelioma and non-small cell lung cancer. Pemetrexed is currently being evaluated for anti-tumor activity in a variety of solid and central nervous system tumors. We studied the plasma and cerebrospinal fluid (CSF) pharmacokinetics of pemetrexed in a non-human primate model that is highly predictive of human CSF penetration. METHODS: Pemetrexed, 20 mg/kg (400 mg/m2), was administered intravenously to four non-human primates. Serial blood samples were obtained from all animals and serial CSF samples were obtained from three animals. Plasma and CSF concentrations of pemetrexed were measured using LC/MS/MS and the resulting concentration versus time data were evaluated using model independent and dependent methods. RESULTS: Pemetrexed disappearance from plasma was best described by a two compartment model with a mean distribution half-life of 13.8 +/- 3.2 min and an elimination half-life of 70.0 +/- 16.0 min. The volume of distribution of and the clearance from the central compartment were 0.066 +/- 0.017 l/kg and 3.6 +/- 0.6 ml/min/kg, respectively. Peak CSF concentrations occurred 40-71 min after the start of the infusion with an average of 0.26 +/- 0.15 microM. CONCLUSION: The CSF penetration of pemetrexed was less than 2% (range 0.33-1.58%), suggesting that it should be used in conjunction with other CNS preventive strategies when used in the treatment of malignancies with a predilection for CNS or leptomeningeal metastases.

    Title The Motor Activity Log-28: Assessing Daily Use of the Hemiparetic Arm After Stroke.
    Date November 2006
    Journal Neurology
    Excerpt

    Data from monkeys with deafferented forelimbs and humans after stroke indicate that tests of the motor capacity of impaired extremities can overestimate their spontaneous use. Before the Motor Activity Log (MAL) was developed, no instruments assessed spontaneous use of a hemiparetic arm outside the treatment setting.

    Title Is the St. Jude Medical Mechanical Valve an Appropriate Choice for Elderly Patients?: A Long-term Retrospective Study Measuring Quality of Life.
    Date September 2006
    Journal The Journal of Heart Valve Disease
    Excerpt

    BACKGROUND AND AIM OF THE STUDY: The selection of a suitable valve substitute in patients requiring valvular heart surgery is an important element in the preoperative decision-making process between cardiologist, surgeon, and patient. Controversy persists regarding the use of mechanical valves in the elderly. With the population living longer, reoperative risk becomes of paramount importance. Quality of life (QOL) considerations are often as important to the patient as longevity. The influence of mechanical valve replacement on QOL in elderly patients has not been well documented. METHODS: Between June 1981 and December 1999, a total of 1,125 consecutive patients aged > or = 65 years (582 men, 543 women; mean age 71.4 +/- 4.9 years) underwent valve replacement with at least one St. Jude Medical (SJM) mechanical valve. Preoperatively, 138 patients (12.3%) were in NYHA class II, 775 (68.9%) in class III, and 212 (18.8%) in class IV. In 535 patients (47.6%), coronary artery disease required surgical intervention. Survivors were administered the Short Form (SF)-36 QOL Survey at follow up, which was 96.1% complete. RESULTS: Hospital mortality was 7.6% (85/1,125). Mean follow up was 5.9 years (range: 9 months to 18.4 years). Mean (+/- SEM) actuarial survival was 70.6 +/- 1.4% at five years, and 40.6 +/- 2.0% at 10 years. Male patients scored significantly higher on the SF-36 than controls in physical (p = 0.012) and mental health (p = 0.004). Comparing female patients with controls revealed no significant difference in physical health; however, they scored higher in mental health than controls (p = 0.001). CONCLUSION: The study results clearly demonstrate that heart surgery in the elderly with the SJM mechanical valve can be accomplished with acceptable hospital mortality, morbidity, and excellent long-term results. Moreover, long-term QOL in elderly patients with a SJM valve can be expected to meet or exceed that of age- and gender-matched controls.

    Title Midterm Outcomes Using the Physio Ring in Mitral Valve Reconstruction: Experience in 492 Patients.
    Date August 2006
    Journal The Annals of Thoracic Surgery
    Excerpt

    BACKGROUND: Mitral valve reconstruction using standardized Carpentier techniques is the treatment of choice for most patients with regurgitant lesions. Demonstrated predictability and stability make it an attractive alternative to valve replacement. The Physio Ring's inherent flexibility provides a viable alternative in the application of remodeling techniques and appears to be physiologically superior to traditional approaches. METHODS: Between April 1994 and October 2000, 492 consecutive patients underwent mitral valve reconstruction using standardized Carpentier techniques with the Carpentier-Edwards Physio Ring (Edwards Lifesciences LLC, Irvine, CA). There were 267 men (54.3%) and 225 women (45.7%). Mean age was 64.2 years (range, 18 to 86). Almost one-half (44.3%) were 70 years of age or over. The mitral valve etiology was congenital in 7 patients (1.4%), myxomatous in 351 patients (71.3%), ischemic in 88 (17.9%), rheumatic in 26 (5.3%), endocarditis in 9 (1.8%), calcific in 8 (1.6%), and other abnormalities in 3 (0.6%). RESULTS: Isolated mitral valve reconstruction was performed in 282 patients (57.3%), with coronary artery bypass grafting (CABG) in 182 (37.0%), with valve replacement in 11 (2.2%), and with CABG and valve replacement in 17 (3.5%). All patients (100.0%) had ring annuloplasty, 263 (53.5%) leaflet resection, 140 (28.5%) chordal resection, 55 (11.2%) chordal transposition, 48 (9.8%) chordal shortening, and 15 (3.0%) commissurotomy. Overall hospital mortality was 3.5% (17 of 492). Postoperative complications included respiratory insufficiency in 55 patients (11.2%), low cardiac output in 13 (2.6%), stroke in 14 (2.8%), reoperation for bleeding in 13 (2.6%), renal insufficiency in 21 (4.3%), and myocardial infarction in 5 (1.0%), and new onset of atrial fibrillation in 74 patients (15.0%). The cumulative follow-up for the series was 1,522.9 patient years and ranged from 1 to 101.0 months (mean, 38.5 months). There were 11 reconstruction failures (2.3%) requiring ring explant. Actuarial survival was 81.5% +/- 2.1% at 4 years and 67.9% +/- 4.6% at 7 years. Freedom from reoperation at 4 years was 81.5% +/- 2.1% and 67.9% +/- 4.6% at 7 years. CONCLUSIONS: Mitral valve reconstruction with the Physio Ring can be accomplished with low hospital mortality and morbidity even in combined procedures. Moreover, the low incidence of reoperation and late cardiac events suggests that the Physio Ring, with its inherent flexibility, offers a definite advantage in the application of remodeling techniques in mitral valve reconstruction.

    Title Comparison of Methods for Determining Renal Function Decline in Early Autosomal Dominant Polycystic Kidney Disease: the Consortium of Radiologic Imaging Studies of Polycystic Kidney Disease Cohort.
    Date July 2006
    Journal Journal of the American Society of Nephrology : Jasn
    Excerpt

    A decline in renal function suggests progression of chronic kidney disease. This can be determined by measured GFR (e.g., iothalamate clearance), serum creatinine (SCr)-based GFR estimates, or creatinine clearance. A cohort of 234 patients with autosomal dominant polycystic kidney disease and baseline creatinine clearance>70 ml/min were followed annually for four visits. Iothalamate clearance, SCr, and creatinine clearance were obtained at each visit. Estimated GFR (eGFR) was determined with the Modification of Diet in Renal Disease (MDRD) and Cockcroft-Gault equations. Renal function slopes had a mean residual SD of 10.7% by iothalamate clearance, 8.2% by MDRD equation, 7.7% by Cockcroft-Gault equation, and 14.8% by creatinine clearance. By each method, a decline in renal function (lowest quintile slope) was compared among baseline predictors. Hypertension was associated with a decline in iothalamate clearance (odds ratio [OR] 5.8; 95% confidence interval [CI] 2.3 to 14), eGFR (OR [MDRD] 2.0 [95% CI 1.0 to 4.2] or OR [Cockcroft-Gault] 1.9 [95% CI 0.9 to 3.9]), and creatinine clearance (OR 2.0; 95% CI 1.0 to 4.2). Each doubling of kidney volume at baseline was associated with a decline in iothalamate clearance (OR 2.4; 95% CI 1.5 to 3.7), eGFR (OR 1.7 [95% CI 1.1 to 2.6] or 2.1 [95% CI 1.4 to 3.3]), and creatinine clearance (OR 1.7; 95% CI 1.1 to 2.5). Predictor associations were strongest with measured GFR. Misclassification from changes in non-GFR factors (e.g., creatinine production, tubular secretion) conservatively biased associations with eGFR. Misclassification from method imprecision attenuated associations with creatinine clearance.

    Title Complement-induced Regulatory T Cells Suppress T-cell Responses but Allow for Dendritic-cell Maturation.
    Date April 2006
    Journal Blood
    Excerpt

    Concurrent activation of the T-cell receptor (TCR) and complement regulator CD46 on human CD4+ T lymphocytes induces Tr1-like regulatory T cells that suppress through IL-10 secretion bystander T-cell proliferation. Here we show that, despite their IL-10 production, CD46-induced T-regulatory T cells (Tregs) do not suppress the activation/maturation of dendritic cells (DCs). DC maturation by complement/CD46-induced Tregs is mediated through simultaneous secretion of GM-CSF and soluble CD40L, factors favoring DC differentiation and reversing inhibitory effects of IL-10. Thus, CD46-induced Tregs produce a distinct cytokine profile that inhibits T-cell responses but leaves DC activation unimpaired. Such "DC-sparing" Tregs could be desirable at host/environment interfaces such as the gastrointestinal tract where their specific cytokine profile provides a mechanism that ensures unresponsiveness to commensal bacteria while maintaining reactivity to invading pathogens.

    Title Fiber, Sex, and Colorectal Adenoma: Results of a Pooled Analysis.
    Date March 2006
    Journal The American Journal of Clinical Nutrition
    Excerpt

    BACKGROUND: Evidence for an association between dietary fiber and colorectal neoplasia has been equivocal, and some data suggest that there may be sex differences in response to fiber. OBJECTIVE: We sought to determine whether fiber affects colorectal adenoma recurrence differently in men and women by combining the study populations of 2 large clinical intervention trials: the Wheat Bran Fiber Trial and the Polyp Prevention Trial. DESIGN: Data from 3209 participants combined from 2 trials were analyzed with logistic regression models to examine the effect of a dietary intervention on colorectal adenoma recurrence in the pooled population as a whole and by sex. RESULTS: The adjusted odds ratio for adenoma recurrence for those in the intervention group of either the Wheat Bran Fiber Trial or the Polyp Prevention Trial was 0.91 (95% CI: 0.78, 1.06). For men, the intervention was associated with statistically significantly reduced odds of recurrence with an odds ratio of 0.81 (95% CI: 0.67, 0.98); for women, no significant association was observed. Using a likelihood-ratio test, we found a statistically significant interaction between intervention group and sex (P = 0.03). CONCLUSION: The results of the current analyses indicate that men may experience more benefit from dietary fiber than do women and may help to explain some of the discrepant results reported in the literature.

    Title Sonographic Assessment of the Severity and Progression of Autosomal Dominant Polycystic Kidney Disease: the Consortium of Renal Imaging Studies in Polycystic Kidney Disease (crisp).
    Date February 2006
    Journal American Journal of Kidney Diseases : the Official Journal of the National Kidney Foundation
    Excerpt

    BACKGROUND: The accuracy and precision of ultrasonography (US) in assessing the severity of autosomal dominant polycystic kidney disease (ADPKD) is unknown. METHODS: US and magnetic resonance imaging (MRI) were performed at baseline and 1 year on 230 subjects with ADPKD. Ellipsoid volume was calculated from US length, width, and depth, and sequential transverse images were used to measure total and cystic volume directly. These were compared with MRI measurements of kidney volume and cystic volume. RESULTS: Variability between different sonographers ranged from 18% to 42%. Correlations between US and MRI volume were 0.88 and 0.89. The SD of the discrepancy from MRI ranged from 21% to 33% and was unrelated to kidney size or body mass. Kidney length was the most reproducible measurement, and its correlation with MRI volume was 0.84. All patients with an US volume less than 700 cm3 had an MRI volume less than 1,000 cm3, and all patients with an US volume greater than 1,700 cm3 had an MRI volume greater than 1,000 cm3. Increases in volume after 1 year were 12% +/- 36% for the ellipsoid method, 6% +/- 29% for the direct method, and 4.2% +/- 7.2% for MRI. Correlation between US and MRI measurement of fractional cyst volume was 0.80. CONCLUSION: Sonographic measurement of kidney volume in patients with ADPKD is inaccurate and lacks the precision necessary to measure short-term disease progression. However, sonography can provide an estimate of kidney volume that reflects severity and prognosis in individual patients.

    Title The Excite Trial: Attributes of the Wolf Motor Function Test in Patients with Subacute Stroke.
    Date November 2005
    Journal Neurorehabilitation and Neural Repair
    Excerpt

    The Wolf Motor Function Test (WMFT) has been used in rehabilitation studies of chronic stroke patients, but until now its psychometric properties have not been evaluated in patients with subacute stroke. Two hundred twenty-nine participants with subacute stroke (3-9 months postinjury) at 7 research sites met inclusion criteria for the EXCITE Trial and were randomized into immediate or delayed (by 1 year) constraint-induced movement therapy treatment. All evaluations were undertaken by assessors standardized in the administration of the WMFT and masked to treatment designation. Participants were also assessed using the Fugl Meyer Motor Assessment (FMA). Delayed group members had measurements repeated 2 weeks following baseline assessment to determine learning or exposure effects. The results demonstrate that the WMFT differentiated higher from lower functioning participants across sites; scores were uninfluenced by hand dominance or affected side. Women exhibited slower performance times than men. The Functional Ability scale (FAS) portion of the WMFT also revealed lower scores among lower functioning participants and women. Minimal changes were observed after repeating the WMFT among delayed group participants 2 weeks later. The FMA revealed similar results when the total group was divided into higher and lower functional levels at its midpoint score of 33. The WMFT discriminates higher from lower functioning participants tested across research sites. Comparable findings using the FMA support the criterion validity of the WMFT.

    Title Magnetic Resonance Measurements of Renal Blood Flow As a Marker of Disease Severity in Autosomal-dominant Polycystic Kidney Disease.
    Date July 2004
    Journal Kidney International
    Excerpt

    BACKGROUND: Autosomal-dominant polycystic kidney disease (ADPKD) is an inherited disorder characterized by renal cyst growth, early development of hypertension, and late occurrence of renal insufficiency. Despite evidence for the importance of nephroangiosclerosis in the progression of renal insufficiency in ADPKD, evaluation of renal blood flow (RBF) as a surrogate marker of disease severity has received little attention. METHODS: Flow phantoms and repeat RBF measurements assessed accuracy and reproducibility. One hundred twenty-seven ADPKD subjects with creatinine clearances >70 mL/min underwent measurements of RBF, total, and cyst renal volumes, and % cyst volumes by magnetic resonance (MR) and of glomerular filtration rate (GFR). Renal vascular resistance (RVR) was calculated. MR blood flow sequences utilized a two-dimensional cine phase-contrast breath-hold pulse sequence perpendicular to the renal arteries. Flow rates were calculated utilizing FLOW software. Volumetric analysis was performed using stereology and region-based thresholding. RESULTS: Excellent accuracy and intraobserver and interobserver reproducibility were demonstrated. Anatomic (total kidney volume, total cyst volume, and % cyst volume), hemodynamic (RBF and RVR), and functional (GFR) parameters were strongly correlated. Left polycystic kidneys were larger and had more severe disease. Regression analysis showed that age, diagnosis of hypertension, anatomic parameters and hemodynamic parameters were significant predictors of GFR. Multiple linear regression analysis identified age and hemodynamic parameters only as separate predictors of GFR. Anatomic, hemodynamic, and functional parameters discriminated between normotensive and hypertensive subjects despite antihypertensive treatments. CONCLUSION: Renal hemodynamic parameters measured by MR correlate with anatomic and functional indices of disease severity, are the strongest predictors of renal function, and deserve further consideration as an outcome measure in clinical trials to guide therapy in ADPKD.

    Title Acute Inflammation and Infection Maintain Circulating Phospholipid Levels and Enhance Lipopolysaccharide Binding to Plasma Lipoproteins.
    Date June 2004
    Journal Journal of Lipid Research
    Excerpt

    Circulating lipoproteins are thought to play an important role in the detoxification of lipopolysaccharide (LPS) by binding the bioactive lipid A portion of LPS to the lipoprotein surface. It has been assumed that hypocholesterolemia contributes to inflammation during critical illness by impairing LPS neutralization. We tested whether critical illness impaired LPS binding to lipoproteins and found, to the contrary, that LPS binding was enhanced and that LPS binding to the lipoprotein classes correlated with their phospholipid content. Whereas low serum cholesterol was almost entirely due to the loss of esterified cholesterol (a lipoprotein core component), phospholipids (the major lipoprotein surface lipid) were maintained at near normal levels and were increased in a hypertriglyceridemic subset of septic patients. The levels of phospholipids found in the LDL and VLDL fractions varied inversely with those in the HDL fraction, and LPS bound predominantly to lipoproteins in the LDL and VLDL fractions when HDL levels were low. Lipoproteins isolated from the serum of septic patients neutralized the bioactivity of the LPS that had bound to them. Our results show that the host response to acute inflammation and infection tends to maintain lipoprotein phospholipid levels and that, despite hypocholesterolemia and reduced HDL levels, circulating lipoproteins maintain their ability to bind and neutralize an important bacterial agonist, LPS.

    Title Plasma and Cerebrospinal Fluid Pharmacokinetic Study of Bnp1350 in Nonhuman Primates.
    Date June 2004
    Journal Cancer Chemotherapy and Pharmacology
    Excerpt

    PURPOSE: BNP1350 (7-[(2-trimethylsilyl)ethyl]-20(S)-camptothecin, karenitecin), a highly lipophilic camptothecin, a high percentage of which is maintained in the active lactone form under physiologic conditions, has recently entered clinical trials in adults and children. BNP1350 has shown significant preclinical antitumor activity against a wide variety of adult and pediatric tumor cell lines. This study was undertaken to define the pharmacokinetics of BNP1350 in both plasma and cerebrospinal fluid (CSF) in a nonhuman primate model. METHODS: Four nonhuman primates with indwelling Ommaya reservoirs received BNP1350, 0.1 mg/kg i.v, administered as a 60-min infusion. Frequent plasma and CSF samples were obtained for quantitation of BNP1350 concentrations using reverse-phase high-pressure liquid chromatography (HPLC). RESULTS: Disappearance of the lactone form from the plasma was biexponential with a mean distribution half-life of 57.5 min (CV +/-33%) and an elimination half-life of 457 min (CV +/-24%). The volume of distribution for the central compartment was 1.36 l/kg (CV +/-27%) and clearance from the central compartment was 10.6 ml/kg per minute (CV +/-28%). The peripheral compartment volume of distribution was 1.96 l/kg (CV +/-8.4%). Peak CSF lactone concentration, which occurred at 12 to 25 min after the end of the infusion, was 0.33 n M (CV +/-71%). CONCLUSIONS: The ratio of the CSF AUC to the plasma AUC was less than 5% (range 0.4% to 3.0%), similar to other highly protein-bound topoisomerase inhibitors such as 9-aminocamptothecin and SN-38 (the active metabolite of irinotecan).

    Title Abnormalities of Thalamic Volume and Shape in Schizophrenia.
    Date June 2004
    Journal The American Journal of Psychiatry
    Excerpt

    OBJECTIVE: Postmortem and neuroimaging studies of schizophrenia have reported deficits in the volume of the thalamus and its component nuclei. However, the pattern of shape change associated with such volume loss has not been investigated. In this study, alterations in thalamic volume, shape, and symmetry were compared in subjects with and without schizophrenia. METHOD: T(1)-weighted magnetic resonance scans were collected in 52 schizophrenia and 65 comparison subjects matched for age, gender, race, and parental socioeconomic status. High-dimensional (large-deformation) brain mapping was used to assess thalamic morphology. RESULTS: Significant differences in thalamic volume, deformities of thalamic shape at the anterior and posterior extremes of the structure, and a significant exaggeration of thalamic asymmetry (i.e., left smaller than right) were found in the schizophrenia subjects. After covarying for total cerebral volume, the difference in thalamic volume became insignificant. When information about thalamic shape was combined with previously collected information about hippocampal shape, the discrimination between schizophrenia patients and comparison subjects was improved. CONCLUSIONS: Thalamic volume was smaller than normal in schizophrenia patients, but only proportionate to reductions in reduced total cerebral volume. The presence of changes in thalamic shape and asymmetry suggest greater pathologic involvement of individual nuclei at its anterior and posterior extremes of the thalamic complex.

    Title Renal Structure in Early Autosomal-dominant Polycystic Kidney Disease (adpkd): The Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease (crisp) Cohort.
    Date April 2004
    Journal Kidney International
    Excerpt

    BACKGROUND: Autosomal-dominant polycystic kidney disease (ADPKD) is characterized by gradual renal enlargement and cyst growth prior to loss of renal function. Standard radiographic imaging has not provided the resolution and accuracy necessary to detect small changes in renal volume or to reliably measure renal cyst volumes. The Consortium for Radiologic Imaging Studies in Polycystic Kidney Disease (CRISP) is longitudinally observing ADPKD individuals using high-resolution magnetic resonance (MR) imaging to determine if change in renal and cyst volumes can be detected over a short period of time, and if they correlate with decline in renal function early in disease. METHODS: Standardization studies were conducted in phantoms and four subjects at each participating clinical center. After, in the full-scale protocol, healthy ADPKD individuals 15 to 45 years old with creatinine clearance>70 mL/min underwent standardized MR renal imaging, renal iothalamate clearance, comprehensive clinical evaluation, and determination of 24-hour urinary albumin and electrolyte excretion. Stereology was used from T1-weighted images to quantify renal volume, and region-growing thresholding was used from T2-weighted images to determine cyst volume. Renal structures were evaluated in relation to demographic, clinical, and biochemical variables using means/medians, standard deviations, and Pearson correlations. RESULTS: Reliability coefficients for MR renal and cyst volume measurements in phantoms were 99.9% and 89.2%, respectively. In the full-scale protocol, 241 ADPKD individuals (145 women and 96 men) were enrolled. Total renal, cyst, and % cyst volume were significantly greater in each decade group. Hypertensive individuals demonstrated greater renal, cyst, and % cyst volume than normotensive subjects. Age-adjusted renal (r = -0.31, P < 0.0001), cyst (r = -0.36, P < 0.0001), and % cyst volume (r = -0.35, P < 0.0001) were inversely related to glomerular filtration rate (GFR). Age-adjusted renal volume (r = 0.42, P < 0.0001), cystic (r = 0.39, P < 0.0001, and % cyst volume (r = 0.41, P < 0.0001) were related with urinary albumin excretion. CONCLUSION: MR measures of renal and cyst volume are reliable and accurate in patients with ADPKD. ADPKD is characterized by significant cystic involvement that increases with age. Structure (renal and cyst volume) and function (GFR) are inversely related and directly related with the presence of hypertension and urinary albumin excretion in individuals with normal renal function.

    Title Transpupillary Thermotherapy Versus Plaque Radiotherapy for Suspected Choroidal Melanomas.
    Date November 2003
    Journal Ophthalmology
    Excerpt

    PURPOSE: To examine the outcomes and complications of transpupillary thermotherapy for treatment of small choroidal melanomas. DESIGN: Retrospective case-matched comparative study and retrospective observational study. PARTICIPANTS: The case-matched study consisted of 36 patients treated with either transpupillary thermotherapy or plaque radiotherapy (18 patients per group). The observational study consisted of 21 patients treated with transpupillary thermotherapy alone (primary transpupillary thermotherapy) and 9 patients treated with transpupillary thermotherapy plus plaque radiotherapy (adjuvant transpupillary thermotherapy). MAIN OUTCOME MEASURES: Visual acuity, local tumor control, and metastasis. RESULTS: The case-matched groups did not differ significantly with respect to age, gender, initial visual acuity, tumor location, or length of follow-up (mean, 33 months for transpupillary thermotherapy vs. 40 months for plaque radiotherapy). There was no significant difference in final visual acuity (P = 0.810) or postoperative visual acuity change (P = 0.919) between the 2 groups. In the observational study, the mean follow-up was 32 months (range, 4-58 months). Indications for primary transpupillary thermotherapy included documented growth (10 patients) and the presence of >/=3 risk factors for growth (11 patients). Retinal complications occurred in 16 patients (76%). The mean posttreatment visual acuity change was minus 2 lines (range, minus 9 to plus 7 lines). Local failure occurred in 6 patients (29%). Local failure was associated with an increased number of transpupillary thermotherapy spots per session (P = 0.023) and decreased tumor pigmentation (P = 0.001). Indications for adjuvant transpupillary thermotherapy included tumor radioresistance (6 patients) and the presence of risk factors for local failure (3 patients). All 9 tumors that received adjuvant transpupillary thermotherapy regressed rapidly, with no local failures. The mean postoperative visual acuity change was -1.9 lines (range, -9 to +5 lines). No patient in either study developed metastasis. CONCLUSIONS: The recent interest in transpupillary thermotherapy as primary therapy for choroidal melanoma is based largely on the assumption that transpupillary thermotherapy may provide better visual outcomes than plaque radiotherapy. However, this study found no significant difference in visual outcomes between transpupillary thermotherapy and plaque radiotherapy. Further, the local failure rate with transpupillary thermotherapy was substantially higher than with plaque radiotherapy. The most promising role for transpupillary thermotherapy seems to be as an adjunct to plaque radiotherapy. The appropriate indications for transpupillary thermotherapy in the management of choroidal melanoma need to be re-evaluated.

    Title Mnsod Polymorphism and Breast Cancer in a Population-based Case-control Study.
    Date October 2003
    Journal Cancer Letters
    Excerpt

    A polymorphism in the signal sequence (Ala-9Val) of the gene encoding the free radical-quenching manganese superoxide dismutase (MnSOD) has been reported to alter the risk for breast cancer. We evaluated this relationship in a population-based case-control study (476 breast cancer cases and 502 controls). Overall, relative risks were not significantly elevated in women with one (RR: 1.27; 95% CI: 0.91-1.77) or two (RR: 1.18; 95% CI: 0.81-1.73) Ala alleles compared to those homozygous for the wild-type Val genotype. Results do not support any overall association of the Ala-9Val MnSOD polymorphism to the development of breast cancer.

    Title Lipopolysaccharide (lps)-binding Protein Inhibits Responses to Cell-bound Lps.
    Date September 2003
    Journal The Journal of Biological Chemistry
    Excerpt

    Lipopolysaccharide (LPS)-binding protein (LBP) is an acute phase reactant that may play a dual role in vivo, both potentiating and decreasing cell responses to bacterial LPS. Whereas low concentrations of LBP potentiate cell stimulation by transferring LPS to CD14, high LBP concentrations inhibit cell responses to LPS. One inhibitory mechanism involves the ability of LBP to neutralize LPS by transferring it to plasma lipoproteins, whereas other inhibitory mechanisms, such as the one described here, do not require exogenous lipoproteins. Here we show that LBP can inhibit monocyte responses to LPS that has already bound to membrane-bound CD14 (mCD14) on the cell surface. LBP caused rapid dissociation of LPS from mCD14 as measured by the ability of LBP to inhibit cross-linking of a radioiodinated, photoactivatable LPS derivative to mCD14. Whereas LBP removed up to 75% of the mCD14-bound LPS in 10 min, this was not accompanied by extensive release of the LPS from the cells. The cross-linking data suggest that much of the LPS that remained bound to the cells was associated with LBP. The ability of LBP to inhibit cell responses could not be explained by its effect on LPS internalization, because LBP did not significantly increase the internalization of the cell-bound LPS. In cell-free LPS cross-linking experiments, LBP inhibited the transfer of LPS from soluble CD14 to soluble MD-2. Our data support the hypothesis that LBP can inhibit cell responses to LPS by inhibiting LPS transfer from mCD14 to the Toll-like receptor 4-MD-2 signaling receptor.

    Title Case-control Study of Endophthalmitis After Cataract Surgery Comparing Scleral Tunnel and Clear Corneal Wounds.
    Date August 2003
    Journal American Journal of Ophthalmology
    Excerpt

    PURPOSE: To study the possible association between clear corneal incision with or without placement of a suture during cataract extraction and postoperative endophthalmitis. DESIGN: Retrospective, comparative, case-controlled study. METHODS: Thirty-eight patients treated for culture-positive, acute post-cataract surgery endophthalmitis, and 371 randomly selected control patients who underwent uncomplicated cataract surgery in the referring community were studied. Incision type and use of suture during cataract surgery of endophthalmitis patients were compared with the controls. The data were analyzed using logistic regression methods. RESULTS: Of the 38 patients with endophthalmitis, 17 patients (45%) had clear corneal incisions and 21 patients (55%) had a scleral tunnel incision. In 371 controls, 76 patients (20%) had clear corneal incisions and 295 patients (80%) had scleral tunnel incisions. Clear corneal incision was associated with a threefold greater risk of endophthalmitis than was scleral tunnel incision (Odds Ratio, 3.36, 95% Confidence Interval = 1.67 to 6.78). The type of incision was significant (chi(2) = 11.53, P =.0007); a clear corneal incision was more frequently associated with endophthalmitis. A subgroup analysis revealed that the presence or absence of a suture was not significant (chi(2) = 1.31, P =.2524). CONCLUSIONS: In this retrospective, case-controlled study, clear corneal incisions were found to be a statistically significant risk factor for acute post-cataract surgery endophthalmitis when compared with scleral tunnel incisions.

    Title High and Differential Expression of Her-2/neu Extracellular Domain in Bilateral Ductal Fluids from Women with Unilateral Invasive Breast Cancer.
    Date July 2003
    Journal Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
    Excerpt

    PURPOSE: Overexpression of HER-2/neu is associated with aggressive diseaseand perhaps with increased risk of breast cancer when presentin benign breast tissue. Breast ductal fluid can be obtained from women by simple nipple aspiration and may be useful for analyzing the microenvironment of the breast. EXPERIMENTAL DESIGN: After obtaining informed consent, we prospectively compared the volume of fluid collected, protein concentration, and level of HER-2/neu expression in nipple aspiration fluid (NAF) samples from both breasts and serum samples in 65 patients with unilateral primary invasive breast cancer (median age, 54 years). HER-2/neu concentrations were determined by immunoassay, with a sensitivity of 0.1 ng/ml. RESULTS: The mean NAF volume obtained and the mean NAF protein concentration were no different in the normal versus the affected breast (62.4 versus 60.4 micro l and 140.9 versus 107.8 mg/ml, respectively). Mean serum HER-2/neu level was 4.36 ng/ml (range, 0-16.8 ng/ml), approximately 50 times less than the mean NAF HER-2/neu level from all patients and all breasts (209.2 ng/ml; range, 1.0-3480.0). NAF HER-2/neu levels were significantly correlated between breasts for each individual patient (r = 0.302; P = 0.038). HER-2/neu-overexpressing tumors produced significantly more HER-2/neu in the affected breast (653.6 ng/ml) than in the unaffected breast (101.7 ng/ml) or serum (3.46 ng/ml; P = 0.016). CONCLUSIONS: Nipple aspiration is a noninvasive method for detecting tumor-specific relevant molecular changes from ductal fluid. The presence of high HER-2/neu levels in the ductal systems of breast cancer patients may have clinical implications for monoclonal antibody directed therapy.

    Title Variation in Cyclooxygenase Expression Levels Within the Colorectum.
    Date June 2003
    Journal Molecular Carcinogenesis
    Excerpt

    The positive association of decreased risk of colorectal cancer with nonsteroidal antiinflammatory drug (NSAID) use, combined with the observation that cyclooxygenase(COX)-2 is present in a majority of colorectal tumors, has led to the proposed use of isozyme-specific COX inhibitors as preventive agents in polyp and tumor formation in the colon. However, the exact biochemical mechanisms and disease stage at which reduced risk is mediated remain somewhat controversial, in part because of the complex biochemical changes that occur during the progression from aberrant crypt to polyp to tumor. In this study, COX-1 and COX-2 protein expression levels were determined in sets of tumor and normal colon tissue. Changes were characterized in COX-1 and COX-2 expression within individuals, in relation to such factors as sex, tumor grade, and location in the colorectum. COX-1 expression levels were found to be significantly reduced in tumors compared to matched normal tissues (Dunn's method, P < 0.05). Additionally, COX-1 expression was decreased in stage T3 tumors as compared to stage T2 tumors (Student's t-test, P = 0.009). Similar to previous reports, COX-2 protein expression was present in 73% of the tumors studied and appeared to be independent of tumor grade and sex. Interestingly, decreased COX-2 expression correlated with tumor occurrence in rectal mucosa (Wilcoxon two-sample test, P < 0.05). These results warrant further investigation, especially the identification of determinants that would predict which populations would be most responsive to COX-2 inhibition as a means of colorectal cancer chemoprevention.

    Title Nipple Aspirate Fluid Cytology in Breast Carcinoma.
    Date May 2003
    Journal Cancer
    Excerpt

    BACKGROUND: Nipple aspirate fluid (NAF) cytology is a simple noninvasive method to study cells exfoliated into the ductal system of the breast. In the current study, the significance of cytologic findings in NAF was determined by correlating them with histopathologic findings from corresponding breast tissue. Cytologic-histologic correlations of NAF were performed in only a few studies. METHODS: Nipple aspirate fluid was collected by breast massaging and by using a breast aspiration device from 74 women with biopsy confirmed intraductal or invasive carcinoma with or without a history of preoperative neoadjuvant chemotherapy. Cytospin preparations were Pap stained. The number of epithelial cells was quantitated and foamy macrophages were semiquantitatively scored. Cytologic findings were categorized as insufficient for diagnosis (less than 10 epithelial cells), benign, mild atypia, marked atypia or suspicious, and malignant. Finally, they were correlated with tissue findings. RESULTS: Nipple aspirate fluid was obtained from 74 women, including 24 who had received preoperative neoadjuvant chemotherapy. The median age of patients was 54 years. A mean volume of 57 microL NAF and a mean of 149 epithelial cells were obtained. Foamy macrophages were present in 51 (70%) of the specimens. There was a significant correlation between the presence of epithelial cells and foamy macrophages (P < 0.001). Patients treated with chemotherapy had fewer epithelial cells in their NAF compared with patients who were not treated with chemotherapy. Thirty specimens (41%) were inadequate for diagnosis, 34 were (46%) benign, 5 (7%) were mildly atypical, 1 (1%) was markedly atypical, and 4 (5%) were malignant. Of the five cases with mildly atypical cytology, three were intraductal papilloma, one was low-grade papillary intraductal carcinoma, and one was low-grade intracystic papillary carcinoma with invasion in the corresponding tissue specimen. The single case with markedly atypical NAF cytology had extensive ductal carcinoma in situ (DCIS). Of the four cases with malignant NAF cytology, two were extensive DCIS and two had invasive carcinoma with extensive DCIS in the breast specimen. Overall, 3 (27%) of 11 cases of DCIS were detected in NAF and only 2 (4%) of 52 invasive carcinomas including the only two cases with extensive DCIS were detected in NAF. CONCLUSION: The probability of detecting malignant cells in NAF is dependent on the extent of DCIS and nipple involvement by DCIS. Nipple aspirate fluid is not a sensitive test for detecting invasive carcinoma of the breast. Atypical cytology in NAF is associated with papillary lesions in the underlying breast.

    Title Evidence for the Presence of Mutagenic Arylamines in Human Breast Milk and Dna Adducts in Exfoliated Breast Ductal Epithelial Cells.
    Date April 2002
    Journal Environmental and Molecular Mutagenesis
    Excerpt

    Aromatic and heterocyclic amines are ubiquitous environmental mutagens present in combustion emissions, fried meats, and tobacco smoke, and are suspect human mammary carcinogens. To determine the presence of arylamines in breast tissue and fluid, we examined exfoliated breast ductal epithelial cells for DNA adducts and matched human milk samples for mutagenicity. Breast milk was obtained from 50 women who were 4-6 weeks postpartum, and exfoliated epithelial-cell DNA was evaluated for bulky, nonpolar DNA adducts by (32)P-postlabeling and thin-layer chromatography. Milk was processed by acid hydrolysis, and the extracted organics were examined in the standard plate-incorporation Ames Salmonella assay using primarily strain YG1024, which detects frameshift mutations and overexpresses aryl amine N-acetyltransferase. DNA adducts were identified in 66% of the specimens, and bulky adducts migrated in a pattern similar to that of 4-aminobiphenyl standards. The distribution of adducts did not vary by NAT2 genotype status. Of whole milk samples, 88% (22/25) had mutagenic activity. Among the samples for which we had both DNA adduct and mutagenicity data, 58% (14/19) of the samples with adducts were also mutagenic, and 85% (11/13) of the mutagenic samples had adducts. Quantitatively, no correlation was observed between the levels of adducts and the levels of mutagenicity. Separation of the milk showed that mutagenic activity was found in 69% of skimmed milk samples but in only 29% of the corresponding milk fat samples, suggesting that the breast milk mutagens were moderately polar molecules. Chemical fractionation showed that mutagenic activity was found in 67% (4/6) of the basic fractions but in only 33% (2/6) of acidic samples, indicating that the mutagens were primarily basic compounds, such as arylamines. Although pilot in nature, this study corroborates previous findings of significant levels of DNA adducts in breast tissue and mutagenicity in human breast milk and indicates that breast milk mutagens may be moderately polar basic compounds, such as arylamines.

    Title Polymorphisms in Glutathione S-transferases (gstm1 and Gstt1) and Survival After Treatment for Breast Cancer.
    Date October 2001
    Journal Cancer Research
    Excerpt

    The response to treatment for breast cancer is likely predicted by a number of disease and tumor tissue characteristics, many of which are under active investigation. One area that has received little attention is that of endogenous capabilities to respond to reactive oxygen species and subsequent byproducts resulting from radiation therapy and a number of chemotherapeutic agents, preventing cytotoxicity toward tumor cells. The glutathione S-transferases are key conjugating enzymes in this response, and GSTM1 and GSTT1 have deletion polymorphisms that result in no enzyme activity. In this retrospective study, we evaluated the role of GSTM1- and GSTT1-null genotypes on disease-free and overall survival among 251 women who received treatment for incident, primary breast cancer. Women were identified through Tumor Registry records and normal archived tissue retrieved for genotyping. Adjusting for age, race, and stage at diagnosis, women with null genotypes for GSTM1 and GSTT1 had reduced hazard of death [adjusted hazard ratio (HR), 0.59; 95% confidence interval (CI), 0.36-0.97; and HR, 0.51; CI, 0.29-0.90, respectively] in relation to those with alleles present. Furthermore, women who were null for both GSTM1 and GSTT1 had one-third the hazard of death of those with alleles for both genes present (adjusted HR, 0.28; 95% CI, 0.11-0.70). Similar relationships were noted for risk of recurrence. These data indicate that interindividual differences in activity of enzymes that prevent therapy-generated reactive oxidant damage may have an important impact on disease recurrence and overall survival.

    Title Plasma Constituents Regulate Lps Binding To, and Release From, the Monocyte Cell Surface.
    Date October 2001
    Journal Journal of Endotoxin Research
    Excerpt

    Innate immunity to Gram-negative bacteria involves regulated mechanisms that allow sensitive but limited responses to LPS. Two important pathways that lead to host cell activation and LPS deactivation involve: (i) LPS interactions with CD14 and Toll-like receptor 4 on cells (activation); and (ii) LPS sequestration by plasma lipoproteins (deactivation). Whereas these pathways were previously thought to be independent and essentially irreversible, we found that they are connected by a third pathway: (iii) the movement of LPS from host cells to plasma lipoproteins. Our data show that, in the presence of human plasma, LPS binds transiently to monocyte surfaces and then moves from the cell surface to plasma lipoproteins. Soluble CD14 enhances LPS release from cells in the presence of lipoproteins, whereas LPS binding protein and phospholipid transfer protein do not. The transfer of cell-bound LPS to lipoproteins is accompanied by reduced cell responses to the LPS, suggesting that the movement of LPS from leukocytes into lipoproteins may attenuate host responses to LPS in vivo. Preliminary data suggest that changes that occur in the plasma after trauma or during sepsis decrease LPS binding to leukocytes while greatly increasing the rate of LPS release from cells.

    Title Plasma Cd14 Decreases Monocyte Responses to Lps by Transferring Cell-bound Lps to Plasma Lipoproteins.
    Date August 2001
    Journal The Journal of Clinical Investigation
    Excerpt

    CD14, a myeloid cell-surface receptor and soluble plasma protein, binds LPS and other microbial molecules and initiates the innate immune response to bacterial invasion. The blood concentration of soluble CD14 (sCD14) increases during the systemic response to infection. Although high sCD14 blood levels have correlated with increased risk of dying from severe sepsis, sCD14 can diminish cell responses to LPS. We show here that in human serum, sCD14 increases the rate at which cell-bound LPS is released from the monocyte surface and binds to plasma lipoproteins. This enhanced rate of LPS efflux is associated with a significant reduction in the ability of monocytes to produce cytokines in response to LPS. Serum from septic patients reduced the LPS-monocyte interaction by as much as tenfold, and depletion of sCD14 from the serum restored LPS-monocyte binding and release kinetics to near normal levels. In serum from septic patients, monocyte-bound LPS also moved more rapidly into lipoproteins, which completely neutralized the biologic activity of the LPS that bound to them. In human plasma, sCD14 thus diminishes monocyte responses to LPS by transferring cell-bound LPS to lipoproteins. Stress-related increases in plasma sCD14 levels may help prevent inflammatory responses within the blood.

    Title Age, Body Mass Index, Race and Other Determinants of Steroid Hormone Variability: the Heritage Family Study.
    Date August 2001
    Journal European Journal of Endocrinology / European Federation of Endocrine Societies
    Excerpt

    OBJECTIVE AND METHODS: To investigate from the HERITAGE Family Study database, 13 steroid hormones (androstane-3alpha, 17beta-diol glucuronide, androsterone glucuronide, cortisol, dehydroepiandrosterone (DHEA), DHEA ester (DHEAE), DHEA sulfate (DHEAS), dihydrotestosterone (DHT), estradiol, 17-hydroxyprogesterone, progesterone, pregnenolone ester, sex hormone binding globulin (SHBG) and testosterone in each sex for their relationships with age, body mass index (BMI), race and key lifestyle variables. Sample sizes varied from 676 to 750 per hormone. Incremental regression methods were used to examine the contributions of the variables to steroid hormone variability. RESULTS: Age was a major predictor for most steroid hormones. The greatest contribution of age was a negative relationship with DHEAS (R(2)=0.39). BMI was also associated with the variability of several steroid hormones, being the most important predictor of SHBG (R(2)=0.20) and of testosterone (R(2)=0.12) concentrations. When age and BMI were included, race still contributed significantly to the variations in cortisol (R(2)=0.02 for men and 0.04 for women), DHT (R(2)=0.02 for men and 0.03 for women), and progesterone (R(2)=0.03 for women). Nevertheless, race appeared to be less important than age and BMI. In addition, lifestyle indicators (food and nutrient intakes, smoking and physical activity) influenced steroid hormone variability. Their contributions, however, were minor in most cases once age, BMI and race had been taken into account. CONCLUSIONS: We conclude that age was the most important factor, followed by BMI, race and lifestyle factors in explaining steroid hormone variability.

    Title Human Cyp1b1 Leu432val Gene Polymorphism: Ethnic Distribution in African-americans, Caucasians and Chinese; Oestradiol Hydroxylase Activity; and Distribution in Prostate Cancer Cases and Controls.
    Date April 2001
    Journal Pharmacogenetics
    Excerpt

    Cytochrome P4501B1 (CYP1B1) is involved in the activation of many carcinogens and in the metabolism of steroid hormones, including 17beta-oestradiol (E2) and testosterone. We report a significant difference in the allele frequencies of two point mutations in the coding region of the CYP1B1 gene among Caucasian (n = 189), African-American (n = 52) and Chinese (Linxian) (n = 109) populations. A (C to G) transversion at position 1666 in exon 3, which results in an amino acid substitution of Leu432 to Val, was present in African-Americans with an allele frequency for Va1432 of 0.75, in Caucasians of 0.43, and in Chinese of 0.17. A (C to T) transition at position 1719 in exon 3, with no amino acid change (Asp449), appeared to be closely linked with the Val432 variant. Results using human lung microsomal preparations from individuals with the CYP1B1Val/Val and CYP1B1Leu/Leu genotypes indicate that Val432 variant may be a high activity allele and thus may contribute to the interindividual differences in CYP1B1 activity. Because CYP1B1 is involved in hormone and carcinogen metabolism, and given the disparate rates of prostate cancer among ethnic groups, we also evaluated the association of the CYP1B1 Leu432Val polymorphism with prostate cancer risk in a pilot case-control study. Among Caucasians, 34% of men with cancer (n = 50) were homozygous for the Val432 polymorphism, while only 12% of matched control subjects (n = 50) had this genotype. These preliminary data indicate that genetic polymorphisms in CYP1B1 might play an important role in human prostate carcinogenesis.

    Title High-fat Diet-induced Muscle Insulin Resistance: Relationship to Visceral Fat Mass.
    Date December 2000
    Journal American Journal of Physiology. Regulatory, Integrative and Comparative Physiology
    Excerpt

    It has been variously hypothesized that the insulin resistance induced in rodents by a high-fat diet is due to increased visceral fat accumulation, to an increase in muscle triglyceride (TG) content, or to an effect of diet composition. In this study we used a number of interventions: fish oil, leptin, caloric restriction, and shorter duration of fat feeding, to try to disassociate an increase in visceral fat from muscle insulin resistance. Substituting fish oil (18% of calories) for corn oil in the high-fat diet partially protected against both the increase in visceral fat and muscle insulin resistance without affecting muscle TG content. Injections of leptin during the last 4 days of a 4-wk period on the high-fat diet partially reversed the increase in visceral fat and the muscle insulin resistance, while completely normalizing muscle TG. Restricting intake of the high-fat diet to 75% of ad libitum completely prevented the increase in visceral fat and muscle insulin resistance. Maximally insulin-stimulated glucose transport was negatively correlated with visceral fat mass (P < 0.001) in both the soleus and epitrochlearis muscles and with muscle TG concentration in the soleus (P < 0.05) but not in the epitrochlearis. Thus we were unable to dissociate the increase in visceral fat from muscle insulin resistance using a variety of approaches. These results support the hypothesis that an increase in visceral fat is associated with development of muscle insulin resistance.

    Title Association Between Survival After Treatment for Breast Cancer and Glutathione S-transferase P1 Ile105val Polymorphism.
    Date November 2000
    Journal Cancer Research
    Excerpt

    A glutathione S-transferase (GST) P1 polymorphism results in an amino acid substitution, Ile105Val; the Val-containing enzyme has reduced activity toward alkylating agents. Cancer patients with the variant enzyme may differ in removal of treatment agents and in outcomes of therapy. We evaluated survival according to GSTP1 genotype among women (n = 240) treated for breast cancer. Women with the low-activity Val/Val genotype had better survival. Compared with Ile/Ile, hazard ratios for overall survival were 0.8 (95% confidence interval, 0.5-1.3) for Ile/Val and 0.3 (95% confidence interval, 0.1-1.0) for Val/Val (P for trend = 0.04). Inherited metabolic variability may influence treatment outcomes.

    Title Lithium Augmentation Fails to Reduce Symptoms in Poorly Responsive Schizophrenic Outpatients.
    Date July 1999
    Journal The Journal of Clinical Psychiatry
    Excerpt

    BACKGROUND: Nearly one third of patients suffering from schizophrenia do not fully respond to antipsychotic medication. Safe, effective, and cost-efficient methods to reduce symptoms are clearly needed; therefore, lithium as an adjunct to fluphenazine decanoate was tested in a placebo-controlled trial in outpatients who were part of the Treatment Strategies of Schizophrenia (TSS) study. METHOD: Forty-one patients with DSM-III schizophrenia or schizoaffective disorder were assigned to either adjunctive lithium or placebo after at least 6 months of fluphenazine decanoate treatment to stabilize symptoms had failed. The trial was designed for 8 weeks of treatment, and patients assigned to placebo could afterward be administered lithium in an 8-week, open-label study. RESULTS: Assessment of the intent-to-treat analysis revealed no significant differences in demographic variables between the lithium and placebo groups. Although both groups showed significant (p = .00135) improvement as measured by total scores on the Brief Psychiatric Rating Scale (BPRS), there were no significant differences in response between the lithium and placebo groups. Patients originally treated with placebo added to neuroleptic did not have significantly greater improvement when receiving open-label adjunctive lithium. CONCLUSION: Although success with lithium augmentation therapy for persistent psychosis has been reported in the past, this study of well-characterized patients showed no benefit for this common strategy, thus indicating that care be used in utilizing lithium augmentation.

    Title Comparison of Dna Adduct Levels Associated with Exogenous and Endogenous Exposures in Human Pancreas in Relation to Metabolic Genotype.
    Date May 1999
    Journal Mutation Research
    Excerpt

    Recently, we examined normal human pancreas tissue for DNA adducts derived from either exogenous chemical exposure and/or endogenous agents. In an effort to explain the different types and levels of DNA adducts formed in the context of individual susceptibility to cancer, we have focused on gene-environment interactions. Here, we report on the levels of hydrophobic aromatic amines (AAs), specifically those derived from 4-aminobiphenyl (ABP), and DNA adducts associated with oxidative stress in human pancreas. Although these adducts have been reported in several human tissues by different laboratories, a comparison of the levels of these adducts in the same tissue samples has not been performed. Using the same DNA, the genotypes were determined for N-acetyltransferase 1 (NAT1), the glutathione S-transferase (GST) M1, GSTP1, GSTT1, and NAD(P)H quinone reductase-1 (NQO1) as possible modulators of adduct levels because their gene products are involved in the detoxification of AAs, lipid peroxidation products and in redox cycling. These results indicate that ABP-DNA adducts, malondialdehyde-DNA adducts, and 8-oxo-2'-deoxyguanosine (8-oxo-dG) adducts are present at similar levels. Of the metabolic genotypes examined, the presence of ABP-DNA adducts was strongly associated with the putative slow NAT1*4/*4 genotype, suggesting a role for this pathway in ABP detoxification.

    Title Manganese Superoxide Dismutase (mnsod) Genetic Polymorphisms, Dietary Antioxidants, and Risk of Breast Cancer.
    Date February 1999
    Journal Cancer Research
    Excerpt

    Oxidative stress, resulting from the imbalance between prooxidant and antioxidant states, damages DNA, proteins, cell membranes, and mitochondria and seems to play a role in human breast carcinogenesis. Dietary sources of antioxidants (chemical) and endogenous antioxidants (enzymatic), including the polymorphic manganese superoxide dismutase (MnSOD), can act to reduce the load of oxidative stress. We hypothesized that the valine-to-alanine substitution that seems to alter transport of the enzyme into the mitochondrion, changing its efficacy in fighting oxidative stress, was associated with breast cancer risk and that a diet rich in sources of antioxidants could ameliorate the effects on risk. Data were collected in a case-control study of diet and breast cancer in western New York from 1986 to 1991. Caucasian women with incident, primary, histologically confirmed breast cancer were frequency-matched on age and county of residence to community controls. Blood specimens were collected and processed from a subset of participants in the study (266 cases and 295 controls). Using a RFLP that distinguishes a valine (V) to alanine (A) change in the -9 position in the signal sequence of the protein for MnSOD, we characterized MnSOD genotypes in relation to breast cancer risk. We also evaluated the effect of the polymorphism on risk among low and high consumers of fruits and vegetables. Premenopausal women who were homozygous for the A allele had a 4-fold increase in breast cancer risk in comparison to those with 1 or 2 V alleles (odds ratio, 4.3; 95% confidence interval, 1.7-10.8). Risk was most pronounced among women below the median consumption of fruits and vegetables and of dietary ascorbic acid and alpha-tocopherol, with little increased risk for those with diets rich in these foods. Relationships were weaker among postmenopausal women, although the MnSOD AA genotype was associated with an almost 2-fold increase in risk (odds ratio, 1.8; confidence interval, 0.9-3.6). No appreciable modification of risk by diet was detected for these older women. These data support the hypothesis that MnSOD and oxidative stress play a significant role in breast cancer risk, particularly in premenopausal women. The finding that risk was greatest among women who consumed lower amounts of dietary antioxidants and was minimal among high consumers indicates that a diet rich in sources of antioxidants may minimize the deleterious effects of the MnSOD polymorphism, thereby supporting public health recommendations for the consumption of diets rich in fruits and vegetables as a preventive measure against cancer.

    Title Comparison of Dna Adduct Levels Associated with Oxidative Stress in Human Pancreas.
    Date October 1998
    Journal Mutation Research
    Excerpt

    DNA adducts associated with oxidative stress are believed to involve the formation of endogenous reactive species generated by oxidative damage and lipid peroxidation. Although these adducts have been reported in several human tissues by different laboratories, a comparison of the levels of these adducts in the same tissue samples has not been carried out. In this study, we isolated DNA from the pancreas of 15 smokers and 15 non-smokers, and measured the levels of 1,N6-etheno(2'-deoxy)guanosine (edA), 3, N4-etheno(2'-deoxy)cytidine (edC), 8-oxo-2'-deoxyguanosine (8-oxo-dG), and pyrimido[1,2-alpha]purin-10(3H)-one (m1G). Using the same DNA, the glutathione S-transferase (GST) M1, GSTT1, and NAD(P)H quinone reductase-1 (NQO1) genotypes were determined in order to assess the role of their gene products in modulating adduct levels through their involvement in detoxification of lipid peroxidation products and redox cycling, respectively. The highest adduct levels observed were for m1G, followed by 8-oxo-dG, edA, and edC, but there were no differences in adduct levels between smokers and non-smokers and no correlation with the age, sex or body mass index of the subject. Moreover, there was no correlation in adduct levels between edA and eC, or between edA or edC and m1G or 8-oxo-dG. However, there was a significant correlation (r=0.76; p<0.01) between the levels of 8-oxo-dG and m1G in human pancreas DNA. Neither GSTM1 nor NQO1 genotypes were associated with differences in any of the adduct levels. Although the sample set was limited, the data suggest that endogenous DNA adduct formation in human pancreas is not clearly derived from cigarette smoking or from (NQO1)-mediated redox cycling. Further, it appears that neither GSTM1 nor GSTT1 appreciably protects against endogenous adduct formation. Together with the lack of correlation between m1G and edA or edC, these data indicate that the malondialdehyde derived from lipid peroxidation may not contribute significantly to m1G adduct formation. On the other hand, the apparent correlation between m1G and 8-oxo-dG and their comparable high levels are consistent with the hypothesis that m1G is formed primarily by reaction of DNA with a base propenal, which, like 8-oxo-dG, is thought to be derived from hydroxyl radical attack on the DNA.

    Title Genetic Polymorphisms in Catechol-o-methyltransferase, Menopausal Status, and Breast Cancer Risk.
    Date June 1998
    Journal Cancer Research
    Excerpt

    Polymorphic catechol-O-methyltransferase (COMT) catalyzes the O-methylation of estrogen catechols. In a case-control study, we evaluated the association of the low-activity allele (COMT(Met)) with breast cancer risk. Compared to women with COMT(Val/Val), COMT(Met/Met) was associated with an increased risk among premenopausal women [odds ratio (OR), 2.1; confidence interval (CI), 1.4-4.3] but was inversely associated with postmenopausal risk (OR, 0.4; CI, 0.2-0.7). The association of risk with at least one low-activity COMT(Met) allele was strongest among the heaviest premenopausal women (OR, 5.7; CI, 1.1-30.1) and among the leanest postmenopausal women (OR, 0.3; CI, 0.1-0.7), suggesting that COMT, mediated by body mass index, may be playing differential roles in human breast carcinogenesis, dependent upon menopausal status.

    Title Exfoliated Ductal Epithelial Cells in Human Breast Milk: a Source of Target Tissue Dna for Molecular Epidemiologic Studies of Breast Cancer.
    Date March 1998
    Journal Cancer Epidemiology, Biomarkers & Prevention : a Publication of the American Association for Cancer Research, Cosponsored by the American Society of Preventive Oncology
    Excerpt

    Studies of biomarkers of putative breast carcinogens, such as DNA adducts, have been limited by the difficulty in obtaining representative ductal epithelial cells (DECs) from breast tissue. In this feasibility study, we sought to ascertain if exfoliated DECs in breast milk could be a source of DNA for biomarker studies. Specimens (n = 38) were collected over 24 h from nursing women, and a questionnaire was administered. Cell pellets were isolated by repeated centrifugation and washing. Pellets were resuspended and incubated for 2 h, with glass adherence used to remove monocytes, resulting in an enrichment of DECs of >80%. Nonadherent cells were removed, washed, and homogenized for DNA isolation. Accurate DNA quantification was performed by 32P-postlabeling of normal nucleotides under conditions of excess ATP. Although there was wide variability in the amounts of DNA recovered, DNA yield was significantly associated with the number of weeks postpartum (P < 0.01), with optimal yield between 6 and 8 weeks after birth. There were no significant associations (P < 0.05) between the number of cells recovered and milk volume, method of collection, or the number of samples in a 24-h period per individual. This study demonstrates that breast milk can be used as a source of DECs for biomarker studies of gene-environment interaction and that sufficient DNA can be recovered to evaluate carcinogen-DNA adducts and to perform genotyping assays. Using this approach, exfoliated DECs may serve as a source of representative cells for studies of breast carcinogenesis and biomarkers of exposure, susceptibility, and effect.

    Title Dendritic Cell Ontogeny: a Human Dendritic Cell Lineage of Myeloid Origin.
    Date December 1997
    Journal Proceedings of the National Academy of Sciences of the United States of America
    Excerpt

    Dendritic cells (DC) have been thought to represent a family of closely related cells with similar functions and developmental pathways. The best-characterized precursors are the epidermal Langerhans cells, which migrate to lymphoid organs and become activated DC in response to inflammatory stimuli. Here, we demonstrate that a large subset of DC in the T cell-dependent areas of human lymphoid organs are nonactivated cells and belong to a separate lineage that can be identified by high levels of the interleukin 3 receptor alpha chain (IL-3Ralphahi). The CD34+IL-3Ralphahi DC progenitors are of myeloid origin and are distinct from those that give rise to Langerhans cells in vitro. The IL-3Ralphahi DC furthermore appear to migrate to lymphoid organs independently of inflammatory stimuli or foreign antigens. Thus, DC are heterogeneous with regard to function and ontogeny.

    Title Age at Onset and Gender of Schizophrenic Patients in Relation to Neuroleptic Resistance.
    Date April 1997
    Journal The American Journal of Psychiatry
    Excerpt

    The age at onset of schizophrenia for males has usually but not always been reported to be less than that for females. Early onset has also been associated with poor response to neuroleptic treatment and worse long-term outcome. The authors compared age at onset in neuroleptic-resistant and -responsive schizophrenic patients to determine whether the gender difference in age at onset is related to response to neuroleptic treatment.

    Title Neuropsychologic Deficits in Schizophrenia: Relation to Social Function and Effect of Antipsychotic Drug Treatment.
    Date December 1996
    Journal Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology
    Excerpt

    Cognitive impairment is present in the majority of schizophrenic patients, even at the onset of psychosis. It is a relatively stable characteristic in most patients, usually with little progression over the course of illness, but sometimes progresses to severe dementia. The results of studies of the effects of typical neuroleptic drugs on cognitive functioning in schizophrenia are conflicting. Clozapine, which has superior antipsychotic effects compared to typical neuroleptic drugs, has been reported to improve executive function, verbal fluency, attention, and recall memory in two of three studies. Cognitive measures predict work function and overall outcome on clozapine as assessed by the Global Assessment Scale and Quality-of-Life Scale in neuroleptic--resistant schizophrenia. Improvement in cognitive function by clozapine may be a major reason for expanding its currently limited utilization.

    Title Clozapine for Treatment-refractory Mania.
    Date July 1996
    Journal The American Journal of Psychiatry
    Excerpt

    OBJECTIVE: The efficacy of clozapine for treatment-resistant mania was examined in a prospective trial for patients with bipolar or schizoaffective disorder. METHOD: The subjects were 25 acutely manic patients with either bipolar disorder (N = 10) or schizoaffective disorder-bipolar subtype (N = 15) for whom lithium, anticonvulsants, and neuroleptics had been ineffective, had produced intolerable side effects, or both. After a 7-day washout, the patients were treated with clozapine monotherapy. They were evaluated over 13 weeks with the Young Mania Rating Scale and the Brief Psychiatric Rating Scale (BPRS). RESULTS: Of the 25 patients, 18 (72%) exhibited marked improvement on the Young Mania Rating Scale, and eight (32%) exhibited marked improvement on the BPRS. The bipolar patients as compared to schizo-affective patients, and the nonrapid as compared to rapid cyclers, had significantly greater improvement in total BPRS score. CONCLUSIONS: These results suggest that clozapine is an effective therapy for treatment-resistant bipolar and schizoaffective mania.

    Title V Beta-specific Immunotoxin Selectively Kills Acetylcholine Receptor-reactive T Lymphocytes from Mice with Experimental Autoimmune Myasthenia Gravis.
    Date May 1995
    Journal International Immunology
    Excerpt

    Immunization of C57BL/6 mice with purified acetylcholine receptor (AChR) is known to induce a T cell-dependent antibody response that results in experimental autoimmune myasthenia gravis (EAMG). Since past observations link V beta 6+ T cells with a prominent AChR epitope specificity, a V beta 6-specific immunotoxin (VIT6) was tested in vitro for its ability to selectively kill monoclonal and polyclonal T cells that demonstrate reactivity against AChR. Results described below clearly demonstrate the ability to selectively kill AChR-reactive T cells based on their expression of a particular V beta-associated antigen receptor.

    Title Cost Effectiveness of Clozapine in Neuroleptic-resistant Schizophrenia.
    Date November 1993
    Journal The American Journal of Psychiatry
    Excerpt

    OBJECTIVE: The goal of this study was to determine whether clozapine is a cost-effective treatment for treatment-resistant schizophrenia. METHOD: Data were collected on 96 treatment-resistant patients with schizophrenia for 2 years before they entered a clozapine treatment study and for at least 2 years after they entered the study. Information about the cost of inpatient and outpatient treatment, housing costs, other costs, and family burden through direct interview or questionnaire of these patients and their families were available for 47 of the 96 patients. Data on lost income and Social Security disability insurance were also obtained. Outcome measures included psychopathology, quality of life, global functioning, work function, and rehospitalization. RESULTS: The cost of treatment was significantly decreased in the patients who continued clozapine treatment for at least 2 years. This was primarily due to a dramatic decrease in the frequency and cost of rehospitalization. Costs were nonsignificantly lower in patients who dropped out of treatment. The estimated total 2-year cost for the 59 patients who continued clozapine treatment, the 34 patients who dropped out, and the three who interrupted treatment decreased from $7,390,206 to $5,719,463, a savings of $8,702/year per patient. There was a decrease in total costs of $22,936/year for the 37 patients who continued clozapine treatment for whom cost data were available. There were no significant changes in lost income or Social Security disability insurance payments in either group. Clozapine produced a marked improvement in Brief Psychiatric Rating Scale total scores as well as positive negative symptom scores, Global Assessment Scale scores, Quality of Life Scale scores, work functioning, capacity for independent living, and rehospitalization rates. CONCLUSIONS: Clozapine is a cost-effective treatment for treatment-resistant schizophrenic patients. Cost savings result almost exclusively from the reduced cost of hospitalization.

    Title Expression and Interactions of the Src Family of Tyrosine Protein Kinases in T Lymphocytes.
    Date December 1991
    Journal Advances in Cancer Research
    Title Lipoproteins of Borrelia Burgdorferi and Treponema Pallidum Activate Cachectin/tumor Necrosis Factor Synthesis. Analysis Using a Cat Reporter Construct.
    Date October 1991
    Journal Journal of Immunology (baltimore, Md. : 1950)
    Excerpt

    Lipoproteins from two pathogenic spirochetes (Borrelia burgdorferi and Treponema pallidum) induced the biosynthesis of TNF in murine macrophages and in permanently transformed macrophages of the cell line RAW 264.7. Induction was studied by measuring the secretion of biologically active TNF and by measuring the activity of the reporter enzyme chloramphenicol acetyltransferase (CAT) produced within macrophages transfected with an endotoxin-responsive CAT construct. Several lines of evidence indicated that the induction of TNF and CAT was attributable to the spirochete lipoproteins rather than to contaminating or endogenous LPS: 1) the dose response curves observed for the lipoproteins were markedly different from those obtained with LPS; 2) lipoprotein-mediated activation was unaffected by amounts of polymyxin B that completely neutralized the induction of TNF and CAT by LPS, 3) low concentrations of the lipoproteins induced TNF in macrophages from endotoxin-unresponsive C3H/HeJ mice as effectively as in macrophages from normal C3H/HeN mice, and 4) isolated spirochete lipoproteins, but not a non-lipoprotein immunogen, were potent inducers of CAT in the transformed macrophages. Moreover, LPS was not detected in the B. burgdorferi lipoprotein mixtures by Limulus amebocyte lysate assay. Proteolytic digestion of the intact bacterial protein preparations only modestly diminished their ability to activate the cells, suggesting that small lipopeptides comprise the biologically active portions of the molecules, as is the case with the murein lipoprotein of Escherichia coli. Through their ability to induce TNF production by macrophages, spirochete lipoproteins may play important roles in the development of the local inflammatory changes and the systemic manifestations that characterize syphilis and Lyme disease.

    Title Expression of P60fyn in Human Platelets.
    Date May 1990
    Journal Oncogene
    Excerpt

    Platelets possess high levels of tyrosine protein kinase activity which has been associated, in part, with the abundant expression of pp60c-src. We report here that in addition to pp60c-src at least one other member of the src family of tyrosine protein kinases, p60fyn, is expressed in platelets. The abundance of p60fyn was estimated to be approximately 20- to 40-fold higher in platelets than in human fibroblasts. In platelets the abundance of p60fyn was determined to be approximately 5- to 10-fold lower than the abundance of pp60c-src. Thrombin-mediated activation of human platelets was found to rapidly elevate the level of detectable phosphotyrosine containing proteins. However, thrombin treatment of platelets did not result in significant alterations in either the abundance or activity of pp60c-src or p60fyn. These observations demonstrate that at least two members of the src family of tyrosine protein kinases (pp60c-src and p60fyn) are expressed in human platelets, but leave unresolved the question of whether these protein kinases play a role in platelet signal transduction events.

    Title Multivariate Time Series Projections of Parameterized Age-specific Fertility Rates.
    Date April 1990
    Journal Journal of the American Statistical Association
    Title Mitral Valve Reconstruction in the Elderly Population.
    Date September 1989
    Journal The Annals of Thoracic Surgery
    Excerpt

    The technique, efficacy, and long-term results of mitral valve reconstruction have been well demonstrated and reported by Carpentier and other investigators. However, most of the results reported have been in patients aged less than 65 years. Between April 1985 and September 1988, we performed mitral valve reconstruction in 176 patients using Carpentier's classification and technique for repair. Ages ranged from 15 to 86 years (mean age, 63 years). Of the repairs, 96/176 (55%) had concomitant cardiac procedures. Patients aged 65 years or more accounted for 52% (92/176) of the population and 35% (65/176) were more than 70 years old. Hospital mortality (30 day) was 4% (4/84) in the group aged less than 65 years. Hospital mortality for the group aged more than 65 years was 12% (11/92), compared with an overall 8.5% mortality. These results suggest an increased morbidity with mitral valve repair in the patients aged more than 65 years, but this group represents an even higher risk group with mitral valve replacement.

    Title The Role of Interleukin 1 in Human B Cell Activation: Inhibition of B Cell Proliferation and the Generation of Immunoglobulin-secreting Cells by an Antibody Against Human Leukocytic Pyrogen.
    Date July 1983
    Journal Journal of Immunology (baltimore, Md. : 1950)
    Excerpt

    The role of factors released by monocytes (M phi) in the activation of human B lymphocytes was examined by studying the effect of an antiserum against human leukocytic pyrogen (LP) on mitogen-stimulated B cell proliferation and the generation of immunoglobulin-secreting cells (ISC) by peripheral blood mononuclear cells (PBM). Antiserum against LP was obtained from rabbits immunized with LP-containing human M phi supernatants. The globulin fraction of this antiserum inhibited pokeweed mitogen- (PWM) stimulated B cell proliferation and the generation of ISC in a concentration-dependent manner, with 50% inhibition of responsiveness observed with 10 micrograms/ml. By contrast, PWM-induced T cell [3H]thymidine incorporation was not inhibited by concentrations of anti-LP as great as 2000 micrograms/ml. The F(ab')2 fraction of anti-LP also inhibited the generation of ISC in response to both PWM and formalinized Staphylococcus aureus, but required 50 micrograms/ml to achieve 50% inhibition. Anti-LP inhibited the generation of ISC only if present during the first 24 hr of a 6 to 7-day incubation; later addition was not inhibitory. Inhibition was more marked in cultures partially depleted of M phi than in whole PBM cultures. Whereas absorption of the anti-LP with PBM failed to remove the capacity to inhibit the generation of ISC, anti-LP-mediated inhibition of responsiveness could be reversed by the addition of crude M phi culture supernatants or a variety of highly purified interleukin 1 (IL 1) preparations, but not by T cell supernatants. These results indicate anti-LP inhibits human B cell activation by removing the requisite M phi-derived factor IL 1 and also confirm that IL 1 plays an essential role in B cell proliferation and the generation of ISC in man.

    Title Acute Chylous Peritonitis.
    Date April 1982
    Journal Journal of Clinical Gastroenterology
    Excerpt

    The extravasation of chyle into the peritoneal cavity is rarely associated with the sudden development of clinical signs and symptoms of peritonitis. A review of the English literature has documented 56 cases of this unusual disorder. We report a recent case at our institution, describing the pertinent clinical, laboratory, and operative findings. The chronic form of chylous ascites, usually associated with malignant obstruction of the lymphatics, does not cause this acute syndrome. With the acute form exploration is usually undertaken because of the clinical findings of peritonitis. A surgically correctable etiology is frequently found, although 55% of the cases have not been clearly associated with a causative factor. In those cases considered idiopathic, the natural history of the disease is spontaneous closure of the chyle leak with regression of the ascites.

    Title Surgical Management of Aortic Valve Disease in the Elderly: A Retrospective Comparative Study of Valve Choice Using Propensity Score Analysis.
    Date
    Journal The Journal of Heart Valve Disease
    Excerpt

    BACKGROUND AND AIM OF THE STUDY: Aortic valve dysfunction is the most common form of valvular heart disease. As the population continues to age, a greater number of patients will become candidates for aortic valve replacement (AVR); hence, prosthetic valve choice becomes of paramount importance. METHODS: A retrospective analysis was conducted on 801 patients aged > or =65 years who underwent isolated AVR or AVR + coronary artery bypass grafting (CABG) between January 1989 and June 2003 with a Carpentier Edwards Perimount (CEP) pericardial bioprosthesis (n = 398) or a St. Jude Medical (SJM) mechanical valve (n = 403). The mean age of CEP patients was 74.5 years (range: 65-89 years), and of SJM patients 73.9 years (range: 65-90 years). The follow up was 96.2% and 96.5% complete for CEP and SJM patients, respectively. Propensity scoring was used to establish homogeneity of the groups and reduce bias. RESULTS: The operative mortality was 4.0% (n = 16) among CEP patients and 6.5% (n = 26) among SJM patients. Predictors of hospital mortality included: peripheral vascular disease (p = 0.018), surgical urgency (p = 0.010), preoperative intra-aortic balloon pump (IABP) (p = 0.010), intraoperative perfusion time (p = 0.046) and intraoperative IABP (p = 0.001). Postoperative morbidities were similar for the two groups. The mean follow up was 72.4 and 59.2 months for CEP and SJM patients, respectively. The five-year actuarial survival was 70.9 +/- 2.3% for CEP and 71.8 +/- 2.4% for SJM patients; at 10 years the actuarial survival was 32.6 +/- 3.3% and 38.2 +/- 3.8%, respectively. Freedom from reoperation for AVR, stroke and non-fatal myocardial infarction was 98.8% (159/161), 99.4% (160/161) and 99.4% (160/161), respectively, in CEP patients, and 100.0% (220/220), 97.7% (215/220) and 97.7% (215/220), respectively, in SJM patients (p = NS). Predictors of late death (>30 days) included chronic obstructive pulmonary disease (p = 0.001) and mechanical valve replacement (p = 0.001). CONCLUSION: In comparable elderly patients, the outcomes of CEP and SJM valves after AVR showed no significant differences in hospital morbidity, mortality, mid-term survival or late cardiac events. However, the cumulative risk of lifelong anticoagulation with a mechanical valve is a serious consideration that must be factored into the selection algorithm.

    Title Progressive Deformation of Deep Brain Nuclei and Hippocampal-amygdala Formation in Schizophrenia.
    Date
    Journal Biological Psychiatry
    Excerpt

    BACKGROUND: Progressive decreases in cortical gray matter volume have been reported in schizophrenia. However, studies of progressive change in deep brain nuclei and hippocampal-amygdala formation have not yielded consistent findings. METHODS: Two high-resolution, T1-weighted magnetic resonance images were collected 2 years apart in 56 schizophrenia and 62 control subjects. Large-deformation high-dimensional brain mapping was used to generate surfaces for deep brain nuclei and hippocampal-amygdala formation at baseline and follow-up. Repeated-measures analysis of variance was used to test for longitudinal changes in volume and shape. RESULTS: The pattern of progressive changes in the deep brain nuclei and hippocampal-amygdala formation in schizophrenia and control subjects was variable. Of the structures that receive direct projections from the cortex, the thalamus, caudate nucleus, nucleus accumbens, and hippocampus showed changes specific to subjects with schizophrenia, and changes in the amygdala and putamen were similar in both groups. Although different at baseline, no progressive change was observed in the globus pallidus, which does not receive direct projections from the cortex. CONCLUSIONS: These findings suggest that the disease process of schizophrenia is associated with progressive effects on brain structure and that brain structures that receive direct, excitatory connections from the cortex may be more likely to show progressive changes, compared with brain structures that receive indirect, inhibitory connections from the cortex. These findings are also somewhat consistent with the hypothesis that overactivity of excitatory pathways in the brain may contribute to the neural degeneration that occurs in at least a subgroup of individuals with schizophrenia.

    Title Impact of Body Composition on Pharmacokinetics of Doxorubicin in Children: a Glaser Pediatric Research Network Study.
    Date
    Journal Cancer Chemotherapy and Pharmacology
    Excerpt

    PURPOSE: We studied the relationship between doxorubicin pharmacokinetics and body composition in children with cancer. PATIENTS AND METHODS: Children between 1 and 21 years of age, receiving doxorubicin as an infusion of any duration <24 h on either a 1-day or 2-day schedule were eligible if they had no significant abnormality of liver function tests, their dose of doxorubicin was not based on ideal body weight or otherwise "capped," and they weighed >/=12 kg. Body composition was measured by dual-energy X-ray absorptiometry. Doxorubicin and doxorubicinol concentration in plasma were measured by high pressure liquid chromatography. NONMEM was used to perform pharmacokinetic model fitting and S-PLUS was used to perform a post hoc analysis to examine the effect of body composition on pharmacokinetic parameters. RESULTS: Twenty-two subjects (16 male; 10 Hispanic, 10 Caucasian, 2 Asian) completed the study. The median age was 15.0 years (range 3.3-21.5), median weight was 51.5 kg (range 12.4-80), median BMI was 19.7 (range 13.2-30.0), and median body fat was 25% (range 15-36). The population mean clearance of doxorubicin was 420 ml/min/m(2). Doxorubicinol but not doxorubicin clearance was lower in patients with body fat greater than 30%. CONCLUSIONS: Doxorubicinol clearance is decreased in children with >30% body fat. This finding is potentially important clinically, because doxorubicinol may contribute significantly to cardiac toxicity after doxorubicin administration. Further study of the body composition on doxorubicin and doxorubicinol pharmacokinetics and on clinical outcomes is warranted.

    Title Plasma and Cerebrospinal Fluid Pharmacokinetics of Mp470 in Non-human Primates.
    Date
    Journal Cancer Chemotherapy and Pharmacology
    Excerpt

    PURPOSE: MP470 is a multi-targeted tyrosine kinase inhibitor with potent activity against mutant c-Kit, PDGFRalpha, Flt3, c-Met and c-Ret that is being evaluated as an anticancer agent. The plasma and cerebrospinal fluid (CSF) pharmacokinetics of MP470 were studied in a non-human primate model that is highly predictive of CSF penetration in humans. METHODS: Oral MP470, 300 mg, was administered to four non-human primates. Serial samples of blood were collected from four animals and CSF samples from three animals for pharmacokinetic studies. Plasma and CSF concentrations were measured using an LC-MS/MS assay. Both model-independent and model-dependent methods were used to analyze the pharmacokinetic data. RESULTS: Following a one-time oral dose of 300 mg, the MP470 plasma area under the curve (AUC) was 1,690 +/- 821 nM h (mean +/- SD). The half-life of MP470 in the plasma was 11.0 +/- 3.4 h. There was no measurable MP470 in the CSF. CONCLUSIONS: Although CSF penetration is minimal, MP470 has demonstrated potent activity against cancer cell lines in vitro and in vivo, and further clinical investigation is warranted.

    Title Measurement Structure of the Wolf Motor Function Test: Implications for Motor Control Theory.
    Date
    Journal Neurorehabilitation and Neural Repair
    Excerpt

    Tools chosen to measure poststroke upper-extremity rehabilitation outcomes must match contemporary theoretical expectations of motor deficit and recovery because an assessment's theoretical underpinning forms the conceptual basis for interpreting its score.

    Title Elevated Cortisol in Older Adults With Generalized Anxiety Disorder Is Reduced by Treatment: A Placebo-controlled Evaluation of Escitalopram.
    Date
    Journal The American Journal of Geriatric Psychiatry : Official Journal of the American Association for Geriatric Psychiatry
    Excerpt

    BACKGROUND:: Generalized anxiety disorder (GAD) is a common disorder in older adults, which has been linked to hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis in this age group. The authors examined whether treatment of GAD in older adults with a selective serotonin reuptake inhibitor (SSRI) corrects this HPA axis hyperactivity. METHODS:: The authors examined adults aged 60 years and older with GAD in a 12-week randomized controlled trial comparing the SSRI escitalopram with placebo. The authors collected salivary cortisol at six daily time points for 2 consecutive days to assess peak and total (area under the curve) cortisol, both at baseline and posttreatment. RESULTS:: Compared with placebo-treated patients, SSRI-treated patients had a significantly greater reduction in both peak and total cortisol. This reduction in cortisol was limited to patients with elevated (above the median) baseline cortisol, in whom SSRI-treated patients showed substantially greater reduction in cortisol than did placebo-treated patients. Reductions in cortisol were associated with improvements in anxiety. Additionally, genetic variability at the serotonin transporter promoter predicted cortisol changes. CONCLUSIONS:: SSRI treatment of GAD in older adults reduces HPA axis hyperactivity. Further research should determine whether these treatment-attributable changes are sustained and beneficial.

    Title Nanoshell-mediated Photothermal Therapy Improves Survival in a Murine Glioma Model.
    Date
    Journal Journal of Neuro-oncology
    Excerpt

    We are developing a novel treatment for high-grade gliomas using near infrared-absorbing silica-gold nanoshells that are thermally activated upon exposure to a near infrared laser, thereby irreversibly damaging cancerous cells. The goal of this work was to determine the efficacy of nanoshell-mediated photothermal therapy in vivo in murine xenograft models. Tumors were induced in male IcrTac:ICR-Prkdc(SCID) mice by subcutaneous implantation of Firefly Luciferase-labeled U373 human glioma cells and biodistribution and survival studies were performed. To evaluate nanoparticle biodistribution, nanoshells were delivered intravenously to tumor-bearing mice and after 6, 24, or 48 h the tumor, liver, spleen, brain, muscle, and blood were assessed for gold content by inductively coupled plasma-mass spectrometry (ICP-MS) and histology. Nanoshell concentrations in the tumor increased for the first 24 h and stabilized thereafter. Treatment efficacy was evaluated by delivering saline or nanoshells intravenously and externally irradiating tumors with a near infrared laser 24 h post-injection. Success of treatment was assessed by monitoring tumor size, tumor luminescence, and survival time of the mice following laser irradiation. There was a significant improvement in survival for the nanoshell treatment group versus the control (P < 0.02) and 57% of the mice in the nanoshell treatment group remained tumor free at the end of the 90-day study period. By comparison, none of the mice in the control group survived beyond 24 days and mean survival was only 13.3 days. The results of these studies suggest that nanoshell-mediated photothermal therapy represents a promising novel treatment strategy for malignant glioma.

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