Geneticist
23 years of experience
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University of Mississippi Medical Center
2500 N State St
Jackson, MS 39216
601-815-2005
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Education ?

Medical School Score Rankings
The University of Texas Southwestern (1987)
  • Currently 4 of 4 apples
Top 25%

Awards & Distinctions ?

Awards  
Outstanding Supporter of Jackson State University
Phi Beta Kappa
Appointments
University of Mississippi School of Medicine
Associate Professor
Associations
American Board of Medical Genetics

Affiliations ?

Dr. Maher is affiliated with 5 hospitals.

Hospital Affilations

Score

Rankings

  • UT Southwestern University Hospital - Zale Lipshy
    5151 Harry Hines Blvd, Dallas, TX 75235
    • Currently 4 of 4 crosses
    Top 25%
  • University Hospital & Clinics-Holmes County
    239 Bowling Green Rd, Lexington, MS 39095
    • Currently 3 of 4 crosses
    Top 50%
  • UT Southwestern St Paul Hospital
  • UT Southwestern Zale Lipshy Hospital
  • University of Mississippi Medical Center
  • Publications & Research

    Dr. Maher has contributed to 61 publications.
    Title De Novo Acta2 Mutation Causes a Novel Syndrome of Multisystemic Smooth Muscle Dysfunction.
    Date November 2010
    Journal American Journal of Medical Genetics. Part A
    Excerpt

    Smooth muscle cells (SMCs) contract to perform many physiological functions, including regulation of blood flow and pressure in arteries, contraction of the pupils, peristalsis of the gut, and voiding of the bladder. SMC lineage in these organs is characterized by cellular expression of the SMC isoform of α-actin, encoded by the ACTA2 gene. We report here on a unique and de novo mutation in ACTA2, R179H, that causes a syndrome characterized by dysfunction of SMCs throughout the body, leading to aortic and cerebrovascular disease, fixed dilated pupils, hypotonic bladder, malrotation, and hypoperistalsis of the gut and pulmonary hypertension.

    Title Rack1 Downregulates Levels of the Pro-apoptotic Protein Fem1b in Apoptosis-resistant Colon Cancer Cells.
    Date May 2010
    Journal Cancer Biology & Therapy
    Excerpt

    Evasion of apoptosis plays an important role in colon cancer progression. Following loss of the Apc tumor suppressor gene in mice, the gene encoding Fem1b is upregulated early in neoplastic intestinal epithelium. Fem1b is a pro-apoptotic protein that interacts with Fas, TNFR1 and Apaf-1, and increased expression of Fem1b induces apoptosis of cancer cells. Fem1b is a homolog of FEM-1, a protein in Caenorhabditis elegans that is negatively regulated by ubiquitination and proteasomal degradation. To study Fem1b regulation in colon cancer progression, we used apoptotis-sensitive SW480 cells, derived from a primary colon cancer, and their isogenic, apoptosis-resistant counterparts SW620 cells, derived from a subsequent metastatic lesion in the same patient. Treatment with proteasome inhibitor increased Fem1b protein levels in SW620 cells, but not in SW480 cells. In SW620 cells we found that endogenous Fem1b co-immunoprecipitates in complexes with RACK1, a protein known to mediate ubiquitination and proteasomal degradation of other pro-apoptotic proteins and to be upregulated in colon cancer. Full-length Fem1b, or the N-terminal region of Fem1b, associated with RACK1 when co-expressed in HEK293T cells, and RACK1 stimulated ubiquitination of Fem1b. RACK1 overexpression in SW620 cells led to downregulation of Fem1b protein levels. Conversely, downregulation of RACK1 led to upregulation of Fem1b protein levels, associated with induction of apoptosis, and this apoptosis was inhibited by blocking Fem1b protein upregulation. In conclusion, RACK1 downregulates levels of the pro-apoptotic protein Fem1b in metastatic, apoptosis-resistant colon cancer cells, which may promote apoptosis-resistance during progression of colon cancer.

    Title Fem1b, a Proapoptotic Protein, Mediates Proteasome Inhibitor-induced Apoptosis of Human Colon Cancer Cells.
    Date February 2010
    Journal Molecular Carcinogenesis
    Excerpt

    In the treatment of colon cancer, the development of resistance to apoptosis is a major factor in resistance to therapy. New molecular approaches to overcome apoptosis resistance, such as selectively upregulating proapoptotic proteins, are needed in colon cancer therapy. In a mouse model with inactivation of the adenomatous polyposis coli (Apc) tumor suppressor gene, reflecting the pathogenesis of most human colon cancers, the gene encoding feminization-1 homolog b (Fem1b) is upregulated in intestinal epithelium following Apc inactivation. Fem1b is a proapoptotic protein that interacts with apoptosis-inducing proteins Fas, tumor necrosis factor receptor-1 (TNFR1), and apoptotic protease activating factor-1 (Apaf-1). Increasing Fem1b expression induces apoptosis of cancer cells, but effects on colon cancer cells have not been reported. Fem1b is a homolog of feminization-1 (FEM-1), a protein in Caenorhabditis elegans that is regulated by proteasomal degradation, but whether Fem1b is likewise regulated by proteasomal degradation is unknown. Herein, we found that Fem1b protein is expressed in primary human colon cancer specimens, and in malignant SW620, HCT-116, and DLD-1 colon cancer cells. Increasing Fem1b expression, by transfection of a Fem1b expression construct, induced apoptosis of these cells. We found that proteasome inhibitor treatment of SW620, HCT-116, and DLD-1 cells caused upregulation of Fem1b protein levels, associated with induction of apoptosis. Blockade of Fem1b upregulation with morpholino antisense oligonucleotide suppressed the proteasome inhibitor-induced apoptosis of these cells. In conclusion, the proapoptotic protein Fem1b is downregulated by the proteasome in malignant colon cancer cells and mediates proteasome inhibitor-induced apoptosis of these cells. Therefore, Fem1b could represent a novel molecular target to overcome apoptosis resistance in therapy of colon cancer.

    Title Randomized Phase Ii Adjuvant Trial of Dose-dense Docetaxel Before or After Doxorubicin Plus Cyclophosphamide in Axillary Node-positive Breast Cancer.
    Date May 2008
    Journal Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
    Excerpt

    An anthracycline-based combination followed by, or combined with, a taxane is the sequence used in most adjuvant chemotherapy regimens. We hypothesized that administering the taxane before the anthracycline combination would be associated with fewer dose reductions and delays than the reverse sequence. To test this hypothesis, a randomized phase II multicenter adjuvant chemotherapy trial was performed.

    Title Retinoic Acid Responsive Genes in the Murine Hepatocyte Cell Line Aml 12.
    Date May 2008
    Journal Gene
    Excerpt

    Retinoic acid (RA) exerts profound effects on multiple aspects of vertebrate development, homeostasis and cellular differentiation. Although the liver is a major target organ for RA, no data exist on global expression of RA-responsive genes in hepatocytes. Therefore, the aim of this study was to characterize RA-responsive genes in a simple system, by using a non-transformed hepatic cell line that is able to express sufficient amounts of endogenous retinoic acid receptors (RARs). For this purpose we used the murine non-transformed hepatocyte cell line AML12. We performed analyses using a cDNA microarray containing 39,000 murine genes. We identified 15 genes that were up-regulated > or =2 fold while 3 were down-regulated > or =2 fold after 3 h treatment with all-trans RA. Following 24 h all-trans RA treatment, 26 genes were up-regulated > or =2 fold, whereas 48 genes were down-regulated > or =2 fold. For some of the genes not previously known to be regulated by RA, we confirmed the regulation by RA using real time PCR. Our data in AML12 cells provide a simple and physiologically relevant system to study RA action, without the influence of neoplastic transformation or artificial RAR over-expression. Furthermore, our data describe novel RA responsive genes and provide insight into the role of RA in important processes such as cholesterol metabolism, bile acid secretion, and oncogenesis, among others, that can be tested in future experiments in vivo.

    Title Thyroid Hormone Responsive Genes in the Murine Hepatocyte Cell Line Aml 12.
    Date September 2007
    Journal Gene
    Excerpt

    Thyroid hormone (T3) plays an important role in gene regulation in the liver. Previous studies have been done in complex systems such as animal models, or in transformed malignant hepatic cell lines in which thyroid hormone receptor (TR) was over-expressed by co-transfection. Therefore, the aim of this study was to characterize T3-responsive genes in a simple system, by using a non-transformed hepatic cell line that is able to express sufficient amounts of endogenous TRs. For this purpose we used the murine non-transformed hepatocyte cell line AML 12. We performed analyses using a cDNA microarray containing 15,000 murine genes. We found 12 genes to be up-regulated and 5 genes to be down-regulated in the presence of T3. For some of the genes not previously known to be regulated by T3, we confirmed the regulation by T3 using real-time PCR. Our data in AML 12 cells provide a simple and physiologically relevant system to study T3 action, without the influence of neoplastic transformation or artificial TR over-expression. Furthermore, our data describe novel T3 responsive genes and provide insight into the role of T3 in important processes such as cholesterol metabolism, bile acid secretion, oncogenesis, among others, that can be tested in future experiments in vivo.

    Title Fem1a is a Candidate Gene for Polycystic Ovary Syndrome.
    Date May 2006
    Journal Gynecological Endocrinology : the Official Journal of the International Society of Gynecological Endocrinology
    Excerpt

    Polycystic ovary syndrome (PCOS) is the most common endocrine disorder among women of reproductive age, and is characterized by infertility, hyperandrogenism and insulin resistance in skeletal muscle. There is evidence for a PCOS gene localized to chromosome 19p13.3. The FEMIA gene maps to chromosome 19p13.3 and is highly expressed in skeletal muscle. FEMIA is a homolog of fem-1, a sex-determination gene of Caenorhabditis elegans that controls masculinization. In a pilot study of Caucasian PCOS patients from our local clinic, we found that one of these five patients exhibited a heterozygous germline missense mutation in FEM1A, designated FEM1A*H500Y. This mutation alters an amino acid conserved from human to C. elegans, and was not found in any of 198 control chromosomes. This missense allele was not found in any of a separate group of 30 PCOS patients from a different regional/ethnic background. Immunostaining of mouse ovary demonstrated that the mouse homolog of FEM1A is expressed in androgen-producing secondary interstitial cells, with a marked increase in expression after puberty, consistent with a key feature of PCOS -- ovarian hyperandrogenism. In conclusion, FEM1A should be considered a candidate gene for PCOS, and more extensive analysis of FEM1A, both coding and regulatory sequences, is warranted in patients and families with PCOS.

    Title The Fem1a Gene is Downregulated in Rhabdomyosarcoma.
    Date December 2005
    Journal Tumour Biology : the Journal of the International Society for Oncodevelopmental Biology and Medicine
    Excerpt

    Rhabdomyosarcoma (RMS) is the most common soft tissue neoplasm of children, and those metastatic at presentation have a poor prognosis. RMS development is related to defective skeletal muscle differentiation, involving a variety of cell signaling and transcriptional control pathways, including aberrant hedgehog signaling. Here we evaluate Fem1a, a gene highly expressed in skeletal muscle, as a candidate for involvement in RMS. Fem1a is a homolog of fem-1, which controls cell fate decisions in the sex determination pathway of Caenorhabditis elegans, a pathway with homology to mammalian hedgehog signaling. We show that Fem1a expression is activated during myocyte differentiation of C2C12 myoblasts, and this expression is largely confined to the terminally differentiating pool, not to the satellite-cell-like quiescent reserve cell pool. We find that the human homolog, FEM1A, is downregulated in all of 8 different human RMS cell lines, including those derived from embryonal and alveolar RMS. Using mouse genetic models of RMS development, we further show that Fem1a is consistently downregulated in primary RMS from Ptch1+/- mice, from p53-/- mice, from p53+/-; Ptch1+/- mice, and from HGF/SF-Ink4a/Arf-/- mice. Therefore, Fem1a downregulation may be involved in, and/or a marker of, an early cell fate defect fundamental to RMS pathogenesis.

    Title Abnormal Glucose Homeostasis and Pancreatic Islet Function in Mice with Inactivation of the Fem1b Gene.
    Date September 2005
    Journal Molecular and Cellular Biology
    Excerpt

    Type 2 diabetes mellitus is a disorder of glucose homeostasis involving complex gene and environmental interactions that are incompletely understood. Mammalian homologs of nematode sex determination genes have recently been implicated in glucose homeostasis and type 2 diabetes mellitus. These are the Hedgehog receptor Patched and Calpain-10, which have homology to the nematode tra-2 and tra-3 sex determination genes, respectively. Here, we have developed Fem1b knockout (Fem1b-KO) mice, with targeted inactivation of Fem1b, a homolog of the nematode fem-1 sex determination gene. We show that the Fem1b-KO mice display abnormal glucose tolerance and that this is due predominantly to defective glucose-stimulated insulin secretion. Arginine-stimulated insulin secretion is also affected. The Fem1b gene is expressed in pancreatic islets, within both beta cells and non-beta cells, and is highly expressed in INS-1E cells, a pancreatic beta-cell line. In conclusion, these data implicate Fem1b in pancreatic islet function and insulin secretion, strengthening evidence that a genetic pathway homologous to nematode sex determination may be involved in glucose homeostasis and suggesting novel genes and processes as potential candidates in the pathogenesis of diabetes mellitus.

    Title Potential Role of Increased Iron Stores in Diabetes.
    Date July 2003
    Journal The American Journal of the Medical Sciences
    Excerpt

    Diabetes mellitus (DM) is an important risk factor for the development of cardiovascular disease. Extensive clinical, epidemiologic, and basic studies suggest that excessive tissue iron stores may contribute to the occurrence and complications of DM. Secondary diabetes occurs in inherited pathologic iron overload syndromes of European- and African-derived populations and is an established complication of transfusional iron overload. Epidemiologic studies have repeatedly shown positive correlation between levels of serum ferritin and those of fasting glucose, insulin, and glycosylated hemoglobin. Iron reduction therapy in hereditary hemochromatosis and transfusional iron overload is associated with improved glucose tolerance and reduced incidence of secondary diabetes. Trials of iron reduction therapy in diabetes mellitus, although limited and inconclusive, have shown clinical improvement in some patients. The current article reviews evidence suggesting that tissue iron contributes to DM and its complications and presents preliminary data that emphasize the potential importance of iron overload in DM of African Americans.

    Title Colorectal Cancer in Russian-speaking Jewish Emigrés: Community-based Screening.
    Date October 2001
    Journal The American Journal of Gastroenterology
    Excerpt

    OBJECTIVES: Colorectal cancer (CRC) screening by fecal occult blood testing and flexible sigmoidoscopy is recommended by many authorities for those older than age 50. Ashkenazi Jews have been shown to have a higher level of CRC and polyps than the general population. A subset of Ashkenazi Jews, Russian-speaking Jewish immigrants to the United States (RJIs), have not been studied extensively for CRC and may have additional risk factors not found in other Ashkenazi populations. METHODS: A retrospective chart review was undertaken of fecal occult blood tests, endoscopy reports, and pathology reports of 132 RJIs and 124 non-RJI controls over age 50 between 1987 and 1999 at the Jewish Hospital of Cincinnati Medical Outpatient Clinic. RESULTS: Mean ages at the time of diagnosis or flexible sigmoidoscopy were 68 yr for RJIs and 66 yr for the non-RJI patients. Of the RJI patients, 38.7% had positive findings: 37 (28.0%) with lesions < 2 cm, five (3.8%) with lesions > 2 cm, and nine (6.8%) with CRC. Of the non-RJI control group patients, 16.9% had positive findings: 16 (12.9%) with lesions < 2 cm, three (2.4%) with lesions > 2 cm, and two (1.6%) with CRC. Age- and sex-matched statistical analysis revealed significantly greater CRC and significantly more polyps > 2 cm for the RJI patients (p < 0.003). This is higher than in other studies of Ashkenazis, which show a 2.3% incidence, and in statistics from the National Cancer Institute, which reveal a national CRC incidence rate for those over age 65 to be 0.30%. CONCLUSIONS: RJIs in our study have polyps > 2 cm and CRC at a rate of 10.6%, as compared with 4.0% for in-clinic controls and a national average of 0.30% for patients over age 65. This suggests a need for more aggressive screening of this patient population for CRC.

    Title Hmg-i/y, a New C-myc Target Gene and Potential Oncogene.
    Date August 2000
    Journal Molecular and Cellular Biology
    Excerpt

    The HMG-I/Y gene encodes the HMG-I and HMG-Y proteins, which function as architectural chromatin binding proteins important in the transcriptional regulation of several genes. Although increased expression of the HMG-I/Y proteins is associated with cellular proliferation, neoplastic transformation, and several human cancers, the role of these proteins in the pathogenesis of malignancy remains unclear. To better understand the role of these proteins in cell growth and transformation, we have been studying the regulation and function of HMG-I/Y. The HMG-I/Y promoter was cloned, sequenced, and subjected to mutagenesis analysis. A c-Myc-Max consensus DNA binding site was identified as an element important in the serum stimulation of HMG-I/Y. The oncoprotein c-Myc and its protein partner Max bind to this site in vitro and activate transcription in transfection experiments. HMG-I/Y expression is stimulated by c-Myc in a Myc-estradiol receptor cell line in the presence of the protein synthesis inhibitor cycloheximide, indicating that HMG-I/Y is a direct c-Myc target gene. HMG-I/Y induction is decreased in Myc-deficient fibroblasts. HMG-I/Y protein expression is also increased in Burkitt's lymphoma cell lines, which are known to have increased c-Myc protein. Like Myc, increased expression of HMG-I protein leads to the neoplastic transformation of both Rat 1a fibroblasts and CB33 cells. In addition, Rat 1a cells overexpressing HMG-I protein form tumors in nude mice. Decreasing HMG-I/Y proteins using an antisense construct abrogates transformation in Burkitt's lymphoma cells. These findings indicate that HMG-I/Y is a c-Myc target gene involved in neoplastic transformation and a member of a new class of potential oncogenes.

    Title The Murine Fem1 Gene Family: Homologs of the Caenorhabditis Elegans Sex-determination Protein Fem-1.
    Date January 1999
    Journal Genomics
    Excerpt

    The pathway controlling sex determination in the nematode Caenorhabditis elegans is a model for the genetic control of cell-fate determination. We report here the cloning and characterization of a new mouse gene family with homology to FEM-1, a signal-transducing regulator in the C. elegans sex-determination pathway. This gene family consists of two known members, designated Fem1a and Fem1b. The highest degree of homology between the two mouse proteins and the nematode protein is in a domain that encodes seven sequential ANK repeats. The Fem1a gene localizes to chromosome 17 and is highly expressed in adult heart and skeletal muscle. The Fem1b gene localizes to chromosome 9 and is highly expressed in adult testis. Both genes are expressed during embryogenesis. The existence of FEM-1 homologs in the mouse raises the possibility that evolutionary conservation of ancient FEM-1 signaling interactions may play a role in vertebrate cell-fate determination.

    Title Long-term Use of High-dose Benzoate and Dextromethorphan for the Treatment of Nonketotic Hyperglycinemia.
    Date May 1998
    Journal The Journal of Pediatrics
    Excerpt

    OBJECTIVE: The objective of this study was to test the hypotheses that reduction of glycine and blocking of the N-methyl-D-aspartate receptor channel complex would be beneficial for both seizure reduction and developmental progress in patients with nonketotic hyperglycinemia. METHODS: We administered benzoate (at doses of 500 to 750 mg/kg/day) and dextromethorphan (at doses of 3.5 to 22.5 mg/kg/day) to four infants with nonketotic hyperglycinemia with follow-up of 3 months to 6 years. RESULTS: Benzoate reduced to normal the glycine concentration in plasma and substantially reduced but did not normalize the glycine concentration in cerebrospinal fluid. Dextromethorphan was a potent anticonvulsant in some but not all patients. There was remarkable interpatient variability in dextromethorphan metabolism. Three patients are living (ages ranging from 4 to 6 years) and are moderately to severely developmentally delayed; two are free of seizures. The third patient, with the slowest development, had intractable seizures for nearly a month before diagnosis, and although seizure-free for 30 months, now has grand-mal seizures. One patient died of intractable seizures at 3 months. CONCLUSIONS: These outcomes suggest that benzoate and dextromethorphan are not uniformly effective in nonketotic hyperglycinemia, but for some patients they improve arousal, decrease or eliminate seizures, and allow for some developmental progress. Trials with additional patients and other receptor channel blockers are warranted.

    Title High-resolution Genetic Mapping of the Cartilage-hair Hypoplasia (chh) Gene in Amish and Finnish Families.
    Date August 1994
    Journal Genomics
    Excerpt

    We recently assigned the gene for cartilage-hair hypoplasia (CHH) to chromosome 9 in Finnish families. Here we have extended and refined our previous linkage analyses by studying 22 Amish and 15 Finnish CHH families and by testing additional markers. The CHH gene maps to 9p in both series and shows no evidence of heterogeneity either within or between the populations. CHH is very closely linked to marker locus D9S163, with no recombinations observed and a combined maximum multipoint lod score of 26.30 for a location at D9S163. Although the odds against a location of the CHH gene between two more distal marker loci, D9S52 and D9S165, are only 48:1, the evidence provided by an observed recombination between the CHH locus and D9S165 and haplotype data at D9S165 and D9S163 in the Amish families allow this interval to be excluded as the location of CHH. We observed strong allelic association between CHH and D9S163 in both Amish and Finnish families, confirming the likely location of the CHH gene very close to this marker. Haplotype analysis of D9S163 and D9S165 in the Amish families suggests that only one mutation accounts for most CHH cases among them, as was expected and as is the case in Finland. Our data do not support the previously suggested hypothesis of a reduced penetrance as an explanation for the deficiency of affected children in the Amish families. We conclude that CHH is a single disease entity in the Amish and Finnish families and that the CHH gene is very close to D9S163 in 9p21-p13.

    Title Learning Peritoneal Physiology by Pharmacological Manipulation.
    Date October 1993
    Journal Peritoneal Dialysis International : Journal of the International Society for Peritoneal Dialysis
    Title Splanchnic Volume, Not Flow Rate, Determines Peritoneal Permeability.
    Date February 1990
    Journal Asaio Transactions / American Society for Artificial Internal Organs
    Excerpt

    To distinguish the effects of splanchnic blood flow rate from those of splanchnic volume on peritoneal transfer rates, measurements were made in rabbits before and after intraperitoneal exposure to sodium chromate. The sodium chromate induced reversible hepatic sinusoidal block with consequent portal venous congestion and stasis, which was demonstrable on histologic sections. Concurrently the ultrafiltration rate, and ultrafiltration coefficient each doubled after chromium even though the dialysate reabsorptive rate increased and the absorptive diffusion of glucose was at least as high as in control dialyses. Chromium induced significant increases in mass transfer coefficients of urea, potassium and phosphate and in protein clearance. These data suggest that splanchnic volume is an important determinant of peritoneal transfer functions and that the hepatic capillaries may contribute appreciably to transfer ordinarily ascribed to peritoneal capillaries alone.

    Title Effects of Histamine and Its Receptor Antagonists on Peritoneal Permeability.
    Date February 1989
    Journal Kidney International
    Excerpt

    Peritoneal fluid and mass transfer rates were studied in rabbits undergoing control dialyses and dialyses with intraperitoneal histamine, or its receptor antagonists alone or in combination. These drugs had negligible effects on peritoneal ultrafiltration and small solute clearances. Histamine raised protein exudation from 1.6 to 2.9 mg/kg/min, an effect blocked by its antagonists which given alone did not lower protein loss. These data demonstrate the existence of histamine receptors in the peritoneal diffusion barrier and show that they do not control transport under baseline conditions, but can be blocked should abnormal histamine release occur. Increased peritoneal permeability with sterile peritonitis was unaffected by ranitidine, suggesting alternative mediators.

    Title Prolonged Intraperitoneal Dwell Decreases Ultrafiltration Coefficient in Rabbits.
    Date July 1988
    Journal American Journal of Kidney Diseases : the Official Journal of the National Kidney Foundation
    Excerpt

    In rabbits undergoing peritoneal dialysis, hypertonic (6% dextrose) dialysis solution increased the net ultrafiltration rate (UF) from 233 to 462 microL/kg/min, which was not proportional to the increment in the osmotic gradient, so the ultrafiltration coefficient decreased. As intraperitoneal dwell of hypertonic dialysate was prolonged, the gross and net UFs and ultrafiltration coefficients decreased, and the UF per dextrose absorption declined. The decrement in UF was multifactorial, including a component of fluid and solute stagnation, increasing the distance over which osmotic forces must exert their effects. Excessively hypertonic dialysis fluid should be used only briefly to achieve ultrafiltration efficiently and to avoid the high dextrose loading.

    Title The Role of the Capillary Wall in Restricting Diffusion of Macromolecules. A Study of Peritoneal Clearance of Dextrans.
    Date July 1988
    Journal Nephron
    Excerpt

    In 5 nephrectomized rabbits the peritoneal clearance of neutral dextrans from plasma to dialysate decreased from 7.8 to 3.3 microliters/kg/min as molecular mass increased from 17,000 to 43,000 daltons, and was relatively constant at 2.8 microliters/kg/min from 49,000 to 97,000 daltons in accord with prior studies. The clearance from dialysate to plasma was measured by determining the distribution volume, which averaged 72 ml/kg, and the plasma concentration 5 h after intraperitoneal instillation. Inward clearances ranged from 11.4 to 19.9 microliter/kg/min, did not correlate well with solute size and were significantly higher than outward clearances. The data suggest that while the capillary wall is the major barrier to macromolecule transfer, absorption can bypass vascular capillaries and occur via the lymphatics. It is suggested that lymphatic flow rate from the peritoneum exceeds 16 microliter/kg/min.

    Title Nephrotic Syndrome Associated with Kimura's Disease.
    Date May 1988
    Journal American Journal of Kidney Diseases : the Official Journal of the National Kidney Foundation
    Excerpt

    Kimura's disease consists of lesions that appear as single or multiple red-brown papules or as subcutaneous nodules with a predilection for the head and neck region. Although it principally affects the skin and soft tissues, there is a high prevalence of associated renal disease. We report a case of nephrotic syndrome associated with Kimura's disease. Our patient is distinctive in that his disease first manifested while residing in the Western hemisphere; the renal disease was characterized as mesangial proliferative glomerulonephritis with renal impairment, and his nephrotic syndrome remitted with standard doses of prednisone.

    Title Contrasting Effects of Amphotericin B and the Solvent Sodium Desoxycholate on Peritoneal Transport.
    Date June 1986
    Journal Nephron
    Excerpt

    To distinguish amphotericin B effects on peritoneal transport from those of the solvent, sodium desoxycholate, dialyses in intact rabbits with either substance added intraperitoneally were compared to controls. Powered amphotericin B added to instilled dialysis fluid increased peritoneal ultrafiltration from 0.31 to 0.44 ml/kg/min (p less than 0.02), but did not affect mass transport (e.g. urea clearance changed from 0.86 to 1.04 ml/kg/min). In contrast, 10 mg of desoxycholate induced peritoneal irritation and raised clearances of urea (0.76-1.34 ml/kg/min), potassium, phosphate and dextrose, but did not affect ultrafiltration. Intraperitoneally, 1 mg/kg of desoxycholate changed clearances inconsistently, but lowered the ultrafiltration rate from 0.33 to 0.21 ml/kg/min. The dialysate-plasma dextrose gradient dissipated faster with 10 mg/kg of desoxycholate. Amphotericin B tended to raise ultrafiltration per osmotic gradient and mass transport of sodium. Selective increase in fluid flux results from amphotericin B, not its solvent.

    Title The Mechanism of Dextrose-enhanced Peritoneal Mass Transport Rates.
    Date November 1985
    Journal Kidney International
    Excerpt

    The mechanism whereby hypertonic dextrose affects peritoneal transport was investigated in a short-term model of peritoneal dialysis using alert intact rabbits. During control (1.5% dextrose) dialyses osmotic ultrafiltration was 0.28 mg/kg/min, the clearance of potassium was 0.98, urea 0.54, phosphate 0.32, and dextrose (reverse) 0.21 ml/kg/min. With 4.25% dextrose, the ultrafiltration rate increased to 0.73 ml/kg/min (P less than 0.02), but solute transport did not increase despite the added convective flux. The posthypertonic exchanges did not differ from control despite the effect of residual dialysate contaminating this peritoneal lavage. By indicator dilution residual volume averaged 12% of total dialysate volume. Acute volume expansion by intravenous dextrose after desoxycorticosterone acetate (DOCA) pretreatment increased the ultrafiltration coefficient, potassium and urea clearances significantly, and DOCA alone was ineffective. It is suggested that in uremic humans hypertonic dextrose dialysis increases peritoneal mass transport rates because the absorbed dextrose causes extracellular volume expansion that cannot be eliminated promptly. No evidence of a direct effect of dextrose augmenting peritoneal permeability was detected.

    Title Acceleration of Peritoneal Solute Transport by Cytochalasin D.
    Date October 1985
    Journal Uremia Investigation
    Excerpt

    Because cytochalasin D affects intercellular junctions the effect of this agent on peritoneal transport was investigated in normal rabbits. Using commercially available dialysis solution, short-term control peritoneal dialyses were compared in the same animals to dialyses in which cytochalasin D was added intraperitoneally. A dose (325-920 micrograms/kg) dependent increase in peritoneal clearances of urea (49% increment at high dose) and of creatinine (67% increment) occurred when cytochalasin D was added. When solute transport was highest at the maximal dose, osmotically induced ultrafiltration decreased significantly to 33% of control values. Cytochalasin D induces aberrations in solute transport that resemble those accompanying and occasionally following peritonitis.

    Title Permselectivity of the Peritoneum to Neutral Dextrans.
    Date June 1985
    Journal Transactions - American Society for Artificial Internal Organs
    Title Amphotericin Selectively Increases Peritoneal Ultrafiltration.
    Date December 1984
    Journal American Journal of Kidney Diseases : the Official Journal of the National Kidney Foundation
    Excerpt

    Because amphotericin B is known to affect transport rates across biologic membranes, the effects of this agent on transport parameters in an animal model of peritoneal dialysis were investigated. When amphotericin B in doses ranging from 0.5 to 25 mg/kg was instilled intraperitoneally with commercial dialysis solution, diffusive clearances of phosphate and urea did not differ from control values measured in the same animals, and only a modest increase in potassium clearance was detected. Ultrafiltration due to the osmotic gradient induced by the dextrose content of the dialysis solution increased significantly to 0.31 mL/kg/min with amphotericin B, compared with control values of 0.18 mL/kg/min. The drug did not affect dextrose transport and the osmotic gradient did not differ in the two groups. Hence, the ultrafiltration coefficient was higher with amphotericin B (14 microL/kg/min/mosm), than during control dialyses (6 microL/kg/min/mosm). Increased water flux was detected at the lowest dose and there was no dose relationship over the range studied. Amphotericin B may be the type of agent that will be clinically useful in patients with reduced peritoneal ultrafiltration capacity, and safer analogues should be explored.

    Title Artificial Organs in Acute Poisoning: to Treat or Not to Treat with Artificial Organs.
    Date April 1983
    Journal Transactions - American Society for Artificial Internal Organs
    Title Aminoglycoside Nephrotoxicity: a Double Blind Prospective Randomized Study of Gentamicin and Tobramycin.
    Date January 1983
    Journal The Journal of Antimicrobial Chemotherapy
    Title Arachidonic Acid Increases Peritoneal Clearances.
    Date April 1982
    Journal Transactions - American Society for Artificial Internal Organs
    Title Panel Conference. Acetate Versus Bicarbonate in Dialysis.
    Date April 1982
    Journal Transactions - American Society for Artificial Internal Organs
    Title Prediction of Radiographic Severity of Renal Osteodystrophy by Serum Values.
    Date August 1981
    Journal International Urology and Nephrology
    Excerpt

    Renal osteodystrophy, a frequent complication of chronic renal failure, is usually assessed by periodic X-rays of bone which are both poorly reproducible and expensive. Seeking a better screening test for osteodystrophy, we evaluated the usefulness of serum alkaline phosphatase as a predictor of bone disease and of hyperparathyroidism. Alkaline phosphatase, despite nonspecificity, correlates with the severity of osteodystrophy and with the increase in serum parathyroid hormone concentration. Serial measurements of alkaline phosphatase can predict changes in these parameters.

    Title Recurrence of Anti-glomerular Basement Membrane Antibody Mediated Glomerulonephritis in an Isograft.
    Date April 1981
    Journal Clinical Immunology and Immunopathology
    Title Modulation of Peritoneal Transport Rates by Prostaglandins.
    Date June 1980
    Journal Advances in Prostaglandin and Thromboxane Research
    Title Prediction of Solute Transport During Peritoneal Dialysis.
    Date April 1980
    Journal Artificial Organs
    Excerpt

    Solute transport, predominantly diffusion, across the peritoneum correlates inversely with molecular weight. Provided that the solute is water soluble, not protein bound, not of unusual density, not ionized, does not have a large hydration shell, and is transported from plasma to dialysate, the peritoneal clearance is predictable over the molecular weight range from 60 to 11,000 daltons. Transport reates that deviate from the predicted can be explained by known physical properties of particular solutes.

    Title Divergent Effects of Catecholamines on Peritoneal Mass Transport.
    Date March 1980
    Journal Transactions - American Society for Artificial Internal Organs
    Excerpt

    In rabbits, intravenous vasopressor doses of dopamine augmented peritoneal clearances of creatinine and urea, suggesting increased mesenteric blood flow and possibly augmented permeability. Intraperitoneal dopamine also accelerated peritoneal transport of urea. Solute transport across the peritoneum was decreased by intravenous infusion of 1-norepinephrine. Intraperitoneal administration of the alpha-adrenergic antagonist phentolamine partially abolished the augmentation of peritoneal clearances induced by intravenous dopamine. The results suggest that in patients undergoing peritoneal dialysis who require vasopressor therapy, dopamine should be preferred to norepinephrine.

    Title Panel Conference: Peritoneal Dialysis: Can We Overcome Its Current Limitations?
    Date March 1980
    Journal Transactions - American Society for Artificial Internal Organs
    Title Effects of Gastrointestinal Hormones on Transport by Peritoneal Dialysis.
    Date February 1980
    Journal Kidney International
    Excerpt

    Because the gastrointestinal hormones are known to dilate the splanchnic vasculature, their effects on transport of water and solutes during peritoneal dialysis were studied in an experimental model, the rabbit. In unanesthetized rabbits, dialysate volume was calculated by isotope dilution, and clearances were estimated by dialysate/plasma concentration ratio factored by minute volume. With isotonic dialysis solution, the mean increment in dialysate volume per minute of intraperitoneal dwell was 0.19 ml/kg/min, and mean clearances of creatinine and urea were 0.71 and 0.90 ml/kg/min, respectively. When administered intravenously, secretin significantly augmented osmotically induced water flux, but not when given intraperitoneally. Neither glucagon nor cholecystokinin affected dialysate volume. Intravenously, but not intraperitoneally, glucagon increased peritoneal clearances of creatinine and urea to more than 150% of control values. Neither cholecystokinin nor secretin augmented significantly peritoneal mass transport when given by either route. The data suggest that the site of acton is the endothelial surface of the membrane, that the mechanisms of augmenting transport involve increased permeability and/or surface area, and that agents which combine an increase in mass transport and capillary filtration coefficient may be clinically useful.

    Title Augmentation of Peritoneal Mass Transport by Dopamine: Comparison with Norepinephrine and Evaluation of Pharmacologic Mechanisms.
    Date January 1980
    Journal The Journal of Laboratory and Clinical Medicine
    Excerpt

    The effect of catecholamines on transport during peritoneal dialysis was studied in unanesthetized rabbits. Intravenous I-norepinephrine consistently decreased peritoneal clearances of urea and creatinine to 84% of control values or less but did not affect osmotically induced water flux. Comparable pressor doses of dopamine increased clearances of urea and creatinine to 145% of control values, whereas osmotic fluid flux increased only slightly. Dopamine also increased urea transport when administered intraperitoneally. The augmentation of solute transport by dopamine was unaffected by simultaneous administration of propranalol, was decreased by phentolamine, and was abolished by haloperidol. Dopamine may be preferable toI-norepinephrine when vasopressor therapy is required during peritoneal dialysis. The augmented transport with dopamine appears to depend on the action of dopamine receptors causing mesenteric vasodilation and in part on alpha-adrenergic receptors simultaneously increasing blood pressure while mesenteric blood flow is maintained.

    Title An Experimental Model for Study of Pharmacologic and Hormonal Influences on Peritoneal Dialysis.
    Date December 1979
    Journal Contributions to Nephrology
    Title Inconsistency in Radiographic Evaluation of Progressive Renal Osteodystrophy.
    Date November 1979
    Journal Clinical Nephrology
    Excerpt

    Five radiologists graded 49 series of bone X-rays of 20 patients with chronic renal failure treated by hemodialysis. There was a high incidence of osteodystrophy which progressed identifiably over intervals exceeding 12 months. The severity grade of osteodystrophy was poorly reproducible among patients, among radiologists, and even between interpretations by the same radiologist after an interval of 10 months. Although the severity of osteodystrophy correlated with serum alkaline phosphatase values, the latter was not an accurate predictor of the severity of the bone lesions. Radiographic reassessment at intervals of one year or less in the asymptomatic patient has less reproducibility than the anticipated changes. More sensitive and reliable techniques are recommended.

    Title Increased Peritoneal Mass Transport with Glucagon Acting at the Vascular Surface.
    Date January 1979
    Journal Transactions - American Society for Artificial Internal Organs
    Title Augmented Peritoneal Mass Transport with Intraperitoneal Nitroprusside.
    Date October 1978
    Journal Journal of Dialysis
    Excerpt

    Lightly restrained, alert New Zealand white rabbits underwent peritoneal dialysis by percutaneous instillation of standard dialysis solution with or without intraperitoneal nitroprusside. Corrected to a mean intraperitoneal dwell time of 36 minutes, mean clearances of creatinine and urea were 0.74 and 0.90 ml/kg/min in six rabbits. With intraperitoneal nitroprusside, 1.13 mg/kg clearances increased to 1.13 and 1.30 ml/kg/min (p less than 0.01) respectively. The 53% increment in creatinine clearance maintained the ratio clearance larger/smaller solute suggesting increased peritoneal permeability and/or area. Lower nitroprusside doses were less effective and not significantly above control. Nitroprusside also increased clearances during hypertonic peritoneal dialysis, but had no effect on osmotically induced water flux. Lavage studies demonstrated a persistent effect of nitroprusside after a single exposure and a sustained effect with repeated use.

    Title The Effect of Dipyridamole on Peritoneal Mass Transport.
    Date November 1977
    Journal Transactions - American Society for Artificial Internal Organs
    Title Influence of Peritoneal Dialysis on Factors Affecting Oxygen Transport.
    Date February 1976
    Journal Nephron
    Excerpt

    To determine the effect of changing concentrations of uremic metabolites on factors affecting oxygen transport, without the effects of extracorporeal blood pumping, we studied five patients before, during and after peritoneal dialysis. Significant decreases in serum urea, creatinine and phosphate and increase in serum bicarbonate were not associated with changes in P50, a reflection of hemoglobin-oxygen affinity. High erythrocyte 2,3-DPG concentrations decreased only slightly. Arterial pO2 increased slightly as negative fluid balance was achieved. The slight changes in oxygen transport parameters with dialysis suggest an interplay of compensatory factors and do not warrant modifying dialysis to limit the correction on acidosis or hyperphosphatemia. Effects on hemoglobin and pO2 resulting from fluid loss can be the dominant influence of peritoneal dialysis on tissue oxygenation.

    Title Effect of Hemodialysis on Factors Influencing Oxygen Transport.
    Date September 1975
    Journal The Journal of Laboratory and Clinical Medicine
    Excerpt

    Ten patients underwent 4 study hemodialyses, one with standard dialysis conditions, one with an isophosphate dialysate, one with simultaneous ammonium chloride loading, and other, after pretreatment, with sodium bicarbonate. Measurement of hemoglobin oxygen affinity (P-50), erythrocyte 2,3-DPG, blood-gasses, and serum chemistries revealed biochemically effective hemodialyses and slight changes in oxygen transport parameters. The P-50 (in vivo) values decreased slightly but significantly (p greater than 0.05) with dialysis. When corrected to pH 7.4, eliminating the Bohr effect, P-50 increased (p greater than 0.05). With unmodified dialysis elevated values of 2,3-DPG (in comparison to normal) decreased, a change that did not correlate with delta-p-50, delta-serum phosphate, or delta-serum creatinine. With standard and isophosphate dialyses Po-2 decreased significantly. The decrease correlated with delta-hydrogen ion concentration and did not occur with dialyses designed to maintain pH constant. Thus, hemodialysis influences many factors that affect oxygen transport in different and counterbalancing directions. These changes are not totally explained by alterations in 2,3-DPG, pH or serum phosphate. Maintenance of acidosis or hyperphosphatemia during dialysis is not recommended.

    Title Natural History of Oliguric Glomerulonephritis.
    Date January 1975
    Journal Perspectives in Nephrology and Hypertension
    Title Fatal Overdose of Propoxyphene Napsylate and Aspirin. A Case Report with Pathologic and Toxicologic Study.
    Date December 1974
    Journal Jama : the Journal of the American Medical Association
    Title Adherence of Blood Components to Dialyzer Membranes: Morphological Studies.
    Date September 1974
    Journal Nephron
    Title Estimation of Weight Loss During Coil Dialysis.
    Date August 1974
    Journal Kidney International
    Title Morphologic Studies of Dialysis Membranes Adherence of Blood Components to Air Rinsed Coils.
    Date October 1973
    Journal Transactions - American Society for Artificial Internal Organs
    Title Etiology and Distribution of Renal Disease in Central Missouri. Case Reports.
    Date April 1973
    Journal Missouri Medicine
    Title Low Renin Hypertension: a State of Inappropriate Secretion of Aldosterone.
    Date February 1972
    Journal The Journal of Laboratory and Clinical Medicine
    Title Renal Function Following Cortical Necrosis in Childhood.
    Date September 1971
    Journal The Journal of Pediatrics
    Title Acute Ethchlorvynol (placidyl) Intoxication.
    Date September 1970
    Journal Annals of Internal Medicine
    Title Intestinal Perforation During Peritoneal Dialysis.
    Date June 1969
    Journal Annals of Internal Medicine
    Title Effects of Uremic Sera on Renal Tubular P-aminohippurate Transport.
    Date July 1967
    Journal Nephron
    Title Renal Tubular Acidosis After Cadaver Kidney Homotransplantation. Studies on Mechanism.
    Date April 1967
    Journal The American Journal of Medicine
    Title Ammonia Metabolism in Renal Failure.
    Date August 1966
    Journal Annals of Internal Medicine
    Title Fem1a and Fem1b: Novel Candidate Genes for Polycystic Ovary Syndrome.
    Date
    Journal Human Reproduction (oxford, England)
    Excerpt

    BACKGROUND Human homologs (FEM1A, FEM1B, FEM1C) of nematode sex determination genes are candidate genes for polycystic ovary syndrome (PCOS). We previously identified a FEM1A mutation (H500Y) in a woman with PCOS; FEM1B has been implicated in insulin secretion. METHODS Women with and without PCOS (287 cases, 187 controls) were genotyped for H500Y and six FEM1A single nucleotide polymorphisms (SNPs), five FEM1B SNPs and five FEM1C SNPs. SNPs and haplotypes were determined and tested for association with PCOS and component phenotypes. RESULTS No subject carried the FEM1A H500Y mutation. FEM1A SNPs rs8111933 (P = 0.001) and rs12460989 (P = 0.046) were associated with an increased likelihood of PCOS whereas FEM1A SNP rs1044386 was associated with a reduced probability of PCOS (P = 0.013). FEM1B SNP rs10152450 and a linked SNP were associated with a reduced likelihood of PCOS (P = 0.005), and lower homeostasis model assessment (HOMA) for beta-cell function (HOMA-%B, P = 0.011) and lower HOMA for insulin resistance (HOMA-IR, P = 0.018). FEM1B SNP rs12909277 was associated with lower HOMA-%B (P = 0.008) and lower HOMA-IR (P = 0.037). Haplotype associations were consistent with SNP results, and also revealed association of FEM1B haplotype TGAGG with increased HOMA-%B (P = 0.007) and HOMA-IR (P = 0.024). FEM1C variants were not associated with PCOS. CONCLUSIONS This study presents evidence suggesting a role for FEM1A and FEM1B in the pathogenesis of PCOS. Only FEM1B variants were associated with insulin-related traits in PCOS women, consistent with prior evidence linking this gene to insulin secretion. Replication of these associations and mechanistic studies will be necessary to establish the role of these genes in PCOS.

    Title Clustering of Sebaceous Gland Carcinoma, Papillary Thyroid Carcinoma and Breast Cancer in a Woman As a New Cancer Susceptibility Disorder: a Case Report.
    Date
    Journal Journal of Medical Case Reports
    Excerpt

    Multiple distinct tumors arising in a single individual or within members of a family raise the suspicion of a genetic susceptibility disorder.

    Title Fem1b Antigen in the Stool of Apc(min) Mice As a Biomarker of Early Wnt Signaling Activation in Intestinal Neoplasia.
    Date
    Journal Cancer Epidemiology
    Excerpt

    Background: Colorectal cancer is preventable by early detection and removal of precursor lesions. Central to early stages of colorectal neoplasia is activation of Wnt signaling, usually due to inactivation of the Apc tumor suppressor gene for which there is an established animal model, the Apc(Min) mouse. Immunodetection in stool of proteins up-regulated by aberrant Wnt signaling, within intestinal epithelial cells shed into the lumen, could be a rational approach to identify biomarkers of early intestinal neoplasia. Fem1b gene expression is up-regulated, following inactivation of Apc, in mouse intestinal epithelium. Methods: We initially screened pooled random stool samples by immunoblotting and found that we could detect, in Apc(Min) mice but not wild-type mice, a fragment of Fem1b protein with an antibody (Li-50) directed against an epitope near the middle of the protein, but not with antibodies directed against N-terminus or C-terminus epitopes. We then evaluated freshly voided individual stool samples collected on four consecutive days from four each of male and female Apc(Min) mice and their wild-type littermates. Results: The Fem1b antigen was detected with the Li-50 antibody in 15/16 samples from male Apc(Min) mice compared to 0/16 samples from male wild-type mice, and in 5/16 samples from female Apc(Min) mice compared to 0/16 samples from female wild-type mice. Conclusions: This study provides proof-of-principle that fragments of proteins, whose expression is increased by aberrant Wnt signaling early in intestinal neoplasia, can be immunodetected in stool. Excreted Fem1b protein fragments may be a useful biomarker for epithelial Wnt signaling and early intestinal neoplasia.

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