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Education ?

Medical School

Awards & Distinctions ?

American Board of Internal Medicine

Publications & Research

Dr. Dave has contributed to 50 publications.
Title A Randomised Trial of Sheathed Versus Standard Forceps for Obtaining Uncontaminated Biopsy Specimens of Microbiota from the Terminal Ileum.
Date November 2011
Journal Gut

The study of intestinal microbiota has been revolutionised by the use of molecular methods, including terminal restriction fragment length polymorphism (T-RFLP) analysis. Microbiota studies of Crohn's disease patients have examined samples from stool or from the neoterminal ileum with a standard biopsy forceps, which could be contaminated by colonic bacteria when the forceps passes through the colonoscope channel.

Title Reply.
Date July 2011
Journal Indian Journal of Psychiatry
Title Primary Sclerosing Cholangitis: Meta-analysis of Diagnostic Performance of Mr Cholangiopancreatography.
Date September 2010
Journal Radiology

To determine the diagnostic accuracy of magnetic resonance cholangiopancreatography (MRCP) for detection of primary sclerosing cholangitis (PSC) in patients with biochemical cholestasis.

Title Association Between Helicobacter Pylori Infection and Inflammatory Bowel Disease: a Meta-analysis and Systematic Review of the Literature.
Date August 2010
Journal Inflammatory Bowel Diseases

Epidemiologic data suggest a protective effect of Helicobacter pylori infection against the development of autoimmune disease. Laboratory data illustrate H. pylori's ability to induce immune tolerance and limit inflammatory responses. Numerous observational studies have investigated the association between H. pylori infection and inflammatory bowel disease (IBD). Our aim was to perform a systematic review and meta-analysis of this association.

Title Hyperammonemic Encephalopathy: a Rare Presentation of Fibrolamellar Hepatocellular Carcinoma.
Date January 2010
Journal The American Journal of the Medical Sciences

Fibrolamellar carcinoma (FLC) is a rare malignant hepatocellular tumor of unknown etiology, arising almost exclusively from noninfected, noncirrhotic liver of young adults. FLC has traditionally been considered to have better survival than hepatocellular carcinoma; however, this notion might be highly erroneous. Patients with metastatic disease at presentation have a dismal prognosis with 5-year survival of only 15%. We describe a case of highly aggressive metastatic FLC that presented as hyperammonemic encephalopathy, which has never been previously reported in the literature.

Title A Study on Toxicity of Gasoline and Gm-10 on Liver of Mice and It's Amelioration by Black Tea Extract.
Date January 2009
Journal Acta Poloniae Pharmaceutica

The aim of present study is to investigate the ameliorative effect of black tea extract on gasoline and GM-10 induced toxicity in liver of mice. Eighty healthy male mice weighing 38-40 g approximately were divided into eight groups which included untreated control and various treated groups. Mice were treated with Gasoline 462 mg/kg/day and GM-10 low dose (206 mg/kg/day) and high dose (412 mg/kg/day) subcutaneously for 30 days. Black tea extract was given as 2 g/100 mL drinking water (2% w/v) instead of pure drinking water. All the animals were sacrificed on 31st day by cervical dislocation and livers were isolated and weighed. Parameters such as lipid peroxidation, catalase, superoxide dismutase, glutathione peroxidase, glutathione and total ascorbic acid were studied. The results revealed dose-dependent toxicity of gasoline and GM-10 on liver. Administration of black tea extract ameliorates this toxicity of gasoline and GM-10 in liver of mice. This proves the effective ameliorative effect of black tea extract.

Title Identification of Symptom Domains in Ulcerative Colitis That Occur Frequently During Flares and Are Responsive to Changes in Disease Activity.
Date October 2008
Journal Health and Quality of Life Outcomes

BACKGROUND: Ulcerative colitis disease activity is determined by measuring symptoms and signs. Our aim was to determine which symptom domains are frequent and responsive to change in the evaluation of disease activity, which are those defined by three criteria: 1) they occur frequently during flares; 2) they improve during effective therapy for ulcerative colitis; and 3) they resolve during remission. METHODS: Twenty-eight symptom domains, 16 from standard indices and 12 novel domains identified by ulcerative colitis patient focus groups, were evaluated. Sixty subjects with ulcerative colitis were surveyed, rating each symptom on the three criteria with a 100 mm Visual Analogue Scale. Frequent and responsive symptoms were defined a priori as those whose median Visual Analogue Scale rating for all 3 criteria was significantly greater than 50. RESULTS: Thirteen of the 28 symptom domains were identified as both frequent in ulcerative colitis flares and responsive to changes in disease activity. Seven of these 13 symptom domains were novel symptoms derived from ulcerative colitis patient focus groups including stool mucus, tenesmus, fatigue, rapid postprandial bowel movements, and inability to differentiate liquid or gas from solid stool when rectal urgency occurs. Ten of the 16 symptom domains from standard indices were either infrequent or unresponsive to changes in disease activity. CONCLUSION: Only some of the symptoms of ulcerative colitis that are important to patients are included in standard indices, and several symptoms currently measured are not frequent or responsive to change in ulcerative colitis patients. Development of survey measures of these symptom domains could significantly improve the assessment of disease activity in ulcerative colitis.

Title A Rapid Method for Isolation of Piperine from the Fruits of Piper Nigrum Linn.
Date July 2008
Journal Journal of Natural Medicines

A simple, rapid and efficient method has been developed for the isolation of piperine from the fruits of Piper nigrum. The method involves extraction of the fruit powder with glacial acetic acid, from which piperine is partitioned into chloroform and subsequently crystallized. The identity of the compound was confirmed by its melting point, comparison of UV, IR, and mass spectral data with those from a reference standard, and co-chromatography with the reference standard using thin-layer chromatography (TLC). The purity of the compound was ascertained by TLC, by recording UV absorption spectra at the start, middle, and end positions of the spot on the plate, and by differential scanning calorimetry (DSC).

Title Protein Isoprenylation Regulates Secretion of Matrix Metalloproteinase 1 from Rheumatoid Synovial Fibroblasts: Effects of Statins and Farnesyl and Geranylgeranyl Transferase Inhibitors.
Date November 2007
Journal Arthritis and Rheumatism

OBJECTIVE: To determine whether protein prenylation (farnesyl/geranylgeranylation) regulates matrix metalloproteinase (MMP) secretion from rheumatoid arthritis (RA) synovial fibroblasts (RASFs), and whether MMP-1 secretion can be regulated by statins or prenyltransferase inhibitors via effects mediated by ERK, JNK, and NF-kappaB. METHODS: RASFs obtained from patients during elective knee replacement surgery were assessed by immunoblotting and/or enzyme-linked immunosorbent assay for secretion of MMP-1 and MMP-13 in the presence of tumor necrosis factor alpha (TNFalpha), interleukin-1beta (IL-1beta), statins, the farnesyl transferase (FT) inhibitor FTI-276 and geranylgeranyl transferase inhibitor GGTI-298, and prenyl substrates (farnesyl pyrophosphate [FPP] and geranylgeranyl pyrophosphate [GGPP]). Activities of JNK and ERK were determined by phosphoimmunoblotting, and NF-kappaB activation was determined by nuclear translocation of the p65 component. RESULTS: FTI-276, but not statins, inhibited RASF secretion of MMP-1, but not MMP-13, following induction with TNFalpha (P = 0.0007) or IL-1beta (P = 0.006). Loading RASFs with FPP to promote farnesylation enhanced MMP-1 secretion. FTI-276 inhibited activation of JNK (P < 0.05) and NF-kappaB (P = 0.02), but not ERK. In contrast, GGTI-298 enhanced, while GGPP inhibited, MMP-1 secretion. FTI-276 and GGTI-298 together had no effect on MMP-1 secretion. Stimulation of RASFs with TNFalpha or IL-1beta led to increased expression and activity of FT. CONCLUSION: Protein farnesylation is required for expression and secretion of MMP-1 from RASFs, via effects on JNK and NF-kappaB. The ability of cytokines to stimulate the expression and activity of FT suggests that FT may be increased in the rheumatoid joint. In contrast, geranylgeranylation down-regulates MMP-1 expression. Statins simultaneously inhibit farnesylation and geranylgeranylation, and in consequence do not inhibit MMP-1 secretion. The ability of FTI-276 to inhibit MMP-1 secretion suggests a potential therapeutic strategy in RA.

Title The Multiple Tasks Test As a Predictor of Falls in Older Adults.
Date February 2006
Journal Gait & Posture

Falls are among the most common and serious problems facing the elderly. The Berg Balance Scale (BBS) is the gold standard in measuring falls risk. With higher functioning elders, a ceiling effect is often evidenced using the BBS. The purpose of this study was to determine if the Multiple Tasks Test (MTT) when used in high functioning community dwelling elderly correlated with the BBS. Secondly, this study assessed the unidimensionality of the MTT. If a relationship existed between the performance of multiple tasks and the potential loss of balance resulting in falls, then the MTT would be more appropriate than the BBS at predicting falls in higher functioning individuals.

Title Resolution of Inflammation: Prostaglandin E2 Dissociates Nuclear Trafficking of Individual Nf-kappab Subunits (p65, P50) in Stimulated Rheumatoid Synovial Fibroblasts.
Date January 2006
Journal Journal of Immunology (baltimore, Md. : 1950)

NF-kappaB transcription factors regulate inflammatory responses to cytokines such as IL-1beta and TNF-alpha. We tested whether PGE2 regulated nuclear localization of individual NF-kappaB subunits, p65 and p50, in synovial fibroblasts harvested from patients with rheumatoid arthritis (RA). IL-1beta/TNF-alpha stimulated the translocation of p65 and p50 from the cytosol to the nucleus of human RA synovial fibroblasts, as well as NF-kappaB activation measured by luciferase reporter assay. PGE2 (10 nM, 6 h) enhanced p50, but inhibited p65 translocation and NF-kappaB activation. In contrast, depletion of endogenous PGE2 by ibuprofen (100 microM) and celecoxib (5 microM) enhanced p65, but inhibited p50 nuclear translocation as well as binding to NF-kappaB DNA binding sites. PGE2 also blocked IL-1beta/TNF-alpha-stimulated ERK activation, and the ERK inhibitor, PD98059, mimicked PGE2 in blocking p65, but enhancing p50 nuclear translocation, suggesting that the effects of PGE2 on p65 and p50 are mediated via effects on ERK. PGE2 also enhanced the expression of IkappaBalpha in an ERK-independent manner, suggesting that PGE2 inhibits NF-kappaB activation by both ERK-dependent and -independent mechanisms. Our data indicate that PGE2 may act to attenuate cytokine-induced inflammatory responses in RA synovial fibroblasts via regulation of the localization of specific NF-kappaB family dimers.

Title Phytochemical Determination and Extraction of Momordica Charantia Fruit and Its Hypoglycemic Potentiation of Oral Hypoglycemic Drugs in Diabetes Mellitus (niddm).
Date February 2005
Journal Indian Journal of Physiology and Pharmacology

Momordica charantia (MC) fruit was subjected to phytochemical and pharmacological interaction studies with oral hypoglycemis in NIDDM patients. Phytochemical, chromatographical analysis and extraction of methanolic MC fruit soft (semi-solid form) in CCl4 + C6H6 solvent system yielded 15 diverse chemical constituents--alkaloids, glycosides, aglycone, tannin, sterol, phenol and protein. The CCl4 + C6H6 MC soft extract was used orally in a dose of 200 mg twice daily (BD) for pharmacological interactions with two diversely acting oral hypoglycemic agents--1) metformin BD and 2) glibenclamide BD in 15 patients of either sex (52-65 years of age) of NIDDM. It was observed that with CCl4 + C6H6 MC soft extract plus half doses of metformin or glibenclamide or both in combination caused hypoglycemia greater than that caused by full doses used in the study with 7 days treatment. Conclusively the extract acts in synergism with oral hypoglycemics and potentiates their hypoglycemia in NIDDM.

Title Beneficial Effects of Yoga Lifestyle on Reversibility of Ischaemic Heart Disease: Caring Heart Project of International Board of Yoga.
Date February 2005
Journal The Journal of the Association of Physicians of India

Yoga based lifestyle modifications have been earlier shown to be beneficial in coronary artery disease in a small number of patients. We evaluated the role of lifestyle modification based on Yoga techniques, stress management and dietary modifications in retardation of coronary artery disease.

Title Mounier-kuhn Syndrome.
Date October 2002
Journal The Indian Journal of Chest Diseases & Allied Sciences

A variant of Mounier-Kuhn syndrome is reported where the patient had bronchiectasis with tracheo-bronchomegaly. The patient also had facial anomalies and asthenozoospermia. This combination has not been reported so far in the literature.

Title Patients with Essential Thrombocythaemia Have an Increased Prevalence of Antiphospholipid Antibodies Which May Be Associated with Thrombosis.
Date September 2002
Journal Thrombosis and Haemostasis

A significant proportion of patients with Essential Thrombocythaemia (ET) have thrombotic complications which have an important impact upon the quality, and duration of their life. We performed a retrospective cross sectional study of the prevalence of antiphospholipid antibodies (APA) in 68 ET patients. Compared to 200 "elderly" controls (>50 years) there was a significant increase in anticardiolipin IgM (p < 0.0001) and anti beta2 glycoprotein I (anti-beta2GPI) IgM (p < 0.0001) antibodies in ET. Thrombosis occurred in 10/20 with APA and 12/48 without, p = 0.04, relative risk 2.0 (95% confidence intervals 1.03-3.86): these patients did not differ in terms of other clinical features. The prevalence of thrombosis in patients with dual APA (6/7) was significant when compared to those with single APA (p = 0.02) and the remaining patients (p < 0.0002). Also anti-beta2GP1 IgM antibodies either alone, or in combination with another APA, were associated with thrombosis (p = 0.02). These results suggest that the prevalence of APA in ET and their influence upon thrombotic risk merit investigation in a larger study.

Title Osteoarthritis or Osteoarthrosis: the Definition of Inflammation Becomes a Semantic Issue in the Genomic Era of Molecular Medicine.
Date March 2002
Journal Osteoarthritis and Cartilage / Oars, Osteoarthritis Research Society
Title Cox-2, No, and Cartilage Damage and Repair.
Date December 2001
Journal Current Rheumatology Reports

The production of nitric oxide (NO) and prostaglandin E2 (PGE(2)) is increased in human osteoarthritis-affected cartilage. These and other inflammatory mediators are spontaneously released by OA cartilage explants ex vivo. The excessive production of nitric oxide inhibits matrix synthesis, and promotes its degradation. Furthermore, by reacting with oxidants such as superoxide anion, nitric oxide promotes cellular injury, and renders the chondrocyte susceptible to cytokine-induced apoptosis. PGE(2) exerts both anabolic and catabolic effects on chondrocytes, depending on the microenvironment and physiological condition. Thus, NO and PGE(2), produced by activated chondrocytes in diseased cartilage, may modulate disease rogression in osteoarthritis, and should therefore be considered potential targets for therapeutic intervention

Title Reversal of Autocrine and Paracrine Effects of Interleukin 1 (il-1) in Human Arthritis by Type Ii Il-1 Decoy Receptor. Potential for Pharmacological Intervention.
Date January 2001
Journal The Journal of Biological Chemistry

Interleukin 1 (IL-1), produced by both synovial cells and chondrocytes, plays a pivotal role in the pathogenesis of cartilage destruction in osteoarthritis (OA). We examined the specific expression and function of IL-1 receptor family-related genes in human joint tissues. Gene array analysis of human normal and OA-affected cartilage showed mRNA expression of IL-1 receptor accessory protein (IL-1RAcp) and IL-1 type I receptor (IL-1RI), but not IL-1 antagonist (IL-1ra) and IL-1 type II decoy receptor (IL-1RII). Similarly, human synovial and epithelial cells showed an absence of IL-1RII mRNA. Functional genomic analyses showed that soluble (s) IL-1RII, at picomolar concentrations, but not soluble TNF receptor:Fc, significantly inhibited IL-1beta-induced nitric oxide (NO) and/or prostaglandin E(2) production in chondrocytes, synovial and epithelial cells. In OA-affected cartilage, the IC(50) for inhibition of NO production by sIL-1RII was 2 log orders lower than that for sIL-1RI. Human chondrocytes that overexpressed IL-1RII were resistant to IL-1-induced IL-1beta mRNA accumulation and inhibition of proteoglycan synthesis. In osteoarthritis, deficient expression by chondrocytes of innate regulators or antagonists of IL-1 such as IL-1ra and IL-1RII (soluble or membrane form) may allow the catabolic effects of IL-1 to proceed unopposed. The sensitivity of IL-1 action to inhibition by sIL-1RII has therapeutic implications that could be directed toward correcting this unfavorable tissue(s) dependent imbalance.

Title Determination of Therapeutic and Growth Promoting Use of Clenbuterol by Plasma Analysis.
Date October 1999
Journal Journal of Veterinary Pharmacology and Therapeutics
Title Determination of Oestrogen Concentrations in Bovine Plasma by a Recombinant Oestrogen Receptor-reporter Gene Yeast Bioassay.
Date September 1999
Journal The Analyst

A recombinant cell yeast bioassay (RCBA) was applied to the generic measurement of bovine plasma oestrogen concentration. Samples were prepared by diethyl ether extraction of plasma following addition of [3H]17 beta-oestradiol as internal standard; organic and aqueous phases were separated by freezing (recovery 97.1 +/- 0.7%) and dried extract reconstituted in culture medium (recovery 31.4 +/- 4.5%). Plasma oestrogen concentrations were measured by incubation of extracts with yeast containing a stable human oestrogen receptor (hER) and a reporter construct comprising an hER response element regulating beta-galactosidase expression. The linearity of response for the analysis of spiked plasma samples using the RCBA, following corrections, is described by y = 0.8994x - 0.111 (r2 = 0.9776, P < 0.0001). Inter-assay variation for endogenous oestrogen was 11.5% for > 1 pg ml-1. Plasma oestrogen concentrations for intact (n = 5) and castrated (n = 3) males were < 0.5 pg ml-1, and 3.7 +/- 2.6 pg ml-1 for luteal phase females (n = 10). Analysis by RCBA of sequential samples from heifers during the reproductive cycle failed to detect the pre-ovulatory increase in plasma 17 beta-oestradiol as determined by radioimmunoassay (RIA) (maximal concentrations 2.09 +/- 2.1 pg ml-1 and 32.6 +/- 14.6 pg ml-1, respectively). Interestingly, when samples were hydrolysed using Helix pomatia glucuronidase the RCBA gave concentrations (29.5 +/- 8.9 pg ml-1) not significantly different to those obtained by RIA. These preliminary findings suggest that a substantial proportion of plasma oestrogen during the pre-ovulatory period may be conjugated. These data indicate the potential of the RCBA to measure biologically active and physiological levels of plasma oestrogens in cattle. One potentially valuable application of this generic oestrogen assay could be in surveillance programmes to detect illegal use of anabolic oestrogens in live-stock where the identity of the analyte may be unknown.

Title Clenbuterol Plasma Pharmacokinetics in Cattle.
Date September 1999
Journal The Analyst

The pharmacokinetics of clenbuterol (Cb) were investigated to determine the extent to which analysis of plasma concentration can be used to discriminate between therapeutic and illicit growth promoting treatment of cattle. Analysis of plasma concentration enabled assessment of the extent of differences in pharmacokinetics between such dosing regimens. Cattle were treated with Cb using either a therapeutic (20 calves, 0.8 microgram Cb kg-1, twice daily in feed for 10 days), or growth promoting (30 calves, 10 micrograms Cb kg-1, twice daily by drench for 20 days) dosing regimens. Blood samples were collected by jugular venepuncture, and plasma Cb concentrations determined by direct enzyme immunoassay. To determine plasma pharmacokinetics, use of a two compartment model was applied to the data and revealed that steady state kinetics were reached after 3 and 5 days following initiation of therapeutic and growth promoting dosing regimens, respectively. Tolerance limit analysis of concentrations during the therapeutic regimen indicated that a plasma Cb concentration greater than 1.63 ng ml-1 would be indicative (p < 0.01) of a growth promoting dose.

Title Beta2-agonist Abuse in Food Producing Animals: Use of in Vitro Liver Preparations to Assess Biotransformation and Potential Target Residues for Surveillance.
Date August 1999
Journal Xenobiotica; the Fate of Foreign Compounds in Biological Systems

1. The biotransformation of [3H]clenbuterol, [3H]salbutamol, [14C]salmeterol and 7-ethoxycoumarin by bovine liver was investigated by incubation with freshly prepared microsomes, suspension and monolayer cultures of isolated hepatocytes, precision-cut (250 microm) and chopped (600 microm) tissue slices. 2. Radio-HPLC analysis indicated that the saligenin beta2-agonists salmeterol and salbutamol were extensively metabolized by all intact cell preparations. A single major product (SmM1) was evident for salmeterol and two unresolved products for salbutamol (SbM1 and SbM2). Differential enzyme hydrolysis studies with Helix pomatia beta-glucuronidase/aryl sulphatase indicated that the main metabolites were glucuronide conjugates. Consistent with this, analysis of metabolites by liquid chromatography-mass spectrometry showed molecular ions ([M+H]+) at m/z 592 for Sm1 and 416 for both Sb1 and Sb2. 3. Comparable studies with clenbuterol revealed three minor metabolites. Prolonged incubations generated products representing, at maximum, 27% biotransformation. Two of the products have been identified as a glucuronide ([M+H]+, m/z 453) and hydroxyclenbuterol ([M+H]+, m/z 293). 4. These findings indicate that in vitro studies provide simple and cost-effective means of evaluating xenobiotic metabolism, and thus of identifying potential target residues to enable surveillance of use of unlicensed veterinary drugs, or prohibited substances in farm animals.

Title Performance on the Rey-osterrieth Complex Figure Test in Alzheimer Disease and Vascular Dementia.
Date June 1999
Journal Neuropsychiatry, Neuropsychology, and Behavioral Neurology

BACKGROUND: Alzheimer disease (AD) and vascular dementia (VaD) are the two most common age-associated dementias. Neuropsychologic studies have demonstrated visuoconstructional impairment in AD and in VaD. OBJECTIVE: This study used the Rey-Osterrieth Complex Figure to assess and compare specific aspects of visuoconstructional deficits in patients with AD, patients with VaD, and normal age-matched subjects. METHOD: Thirteen normal controls, 20 patients with AD, and 20 patients with VaD were given a neuropsychologic battery as part of a comprehensive evaluation for dementia. The groups were similar in age and education, and the VaD and AD groups had comparable levels of dementia. Based on their previous research on visual deficits in AD, the authors devised a new scoring system that divided the Rey-Osterrieth Complex Figure into six perceptual categories: right, left, upper, lower, basic gestalt, and inner detail. RESULTS: Patients with AD and patients with VaD had significant deficits in all six Rey-Osterrieth Complex Figure scoring categories compared with normal controls. Patients with AD exhibited a pattern of deficits similar to that of patients with VaD, with one significant exception: The patients with AD had increased left-sided errors or inattention. CONCLUSIONS: These results suggest that left hemispatial inattention contributes to impaired performance on visuoconstructional tasks in AD.

Title Regulation of Cytosolic Cox-2 and Prostaglandin E2 Production by Nitric Oxide in Activated Murine Macrophages.
Date May 1999
Journal Journal of Immunology (baltimore, Md. : 1950)

Murine macrophages (RAW 264.7) when stimulated with LPS show 90% distribution of cyclooxygenase-2 (COX-2) in the nuclear fraction and approximately 10% in the cytosolic fraction. Further analysis of this cytosolic fraction at 100,000 x g indicates that the COX-2 is distributed both in the 100,000 x g soluble fraction and membrane fraction. Stimulation of RAW 264.7 cells with LPS in the presence of inducible nitric oxide synthase inhibitor L-NMMA at concentrations that inhibit nitrite accumulation by </=80% is inadequate to augment PGE2 production. However, inhibition of nitrite accumulation by >/=85% with higher concentrations of L-NMMA shows 1) up-regulation of PGE2 production, 2) accumulation of COX-2 protein in the 100,000 x g soluble and membrane fractions of the cytosolic fraction, and 3) with no significant effects on the accumulation of COX-2 mRNA. These experiments suggest that low concentrations of nitric oxide (10-15% of the total) attenuate PGE2 production in response to LPS in RAW 264.7 cells. This inhibition is, in part, due to decreased expression of cytosolic COX-2 protein.

Title Analysis of Di-n-butylphthalate Biotransformation in Cattle by Liquid Chromatography/ion Trap Mass Spectrometry/mass Spectrometry.
Date October 1998
Journal Journal of Mass Spectrometry : Jms

The nature of products of contamination intake were investigated in cattle dosed with [14C]di-n-butylphthalate (DBP). Radio-labelled metabolites were extracted from bile, faeces, plasma and urine onto solid-phase media, fractionated by ion-exchange chromatography, separated by reverse phase HPLC and analysed by negative ion atmospheric pressure chemical ionization mass spectrometry(n) (LCQ, Finnigan). All matrices contained a common major metabolite [deprotonated molecular ion (M-H)- m/z 221] which coeluted with and had an identical daughter ion spectrum to reference monobutylphthalate (MBP). MBP was metabolised to a beta-glucuronidase sensitive compound (M-H)- m/z 397 whose spectrum contained daughter ions (m/z 175 and 221) consistent with the parent glucuronide. A further three beta-glucuronidase resistant radio-labelled metabolites were also produced (M-H- m/z 165, 193 and 237); comparison of daughter ion spectra with those of reference MBP and phthalic acid indicated identity with phthalic acid, monoethylphthalate (MEP) and monohydroxybutylphthalate (MHBP) respectively. The presence of a benzoate daughter ion (m/z 121) in all spectra was indicative of side chain biotransformation. Both MBP and MEP contained a phthalate daughter ion (m/z 165) indicating loss of a butyl and ethyl side chain respectively. A daughter ion of m/z 89 derived from the side chain provided evidence that the third metabolite was MHBP. Incubation of DBP with isolated bovine hepatocytes produced the same metabolites and provided relatively clean samples for LC/MSn analysis. Detection of these DBP metabolites in meat or dairy food products will provide evidence for environmental exposure and biotransformation in vivo, whereas the presence of the parent compound would suggest contamination during food processing and packaging.

Title Biotransformation, Tissue Distribution, and Persistence of 4-nonylphenol Residues in Juvenile Rainbow Trout (oncorhynchus Mykiss).
Date May 1998
Journal Drug Metabolism and Disposition: the Biological Fate of Chemicals

Alkylphenols are weak oestrogenic environmental contaminants and have been implicated in the disruption of endocrine function in wildlife. The influence of biotransformation, tissue distribution, and elimination on biological activity was investigated in juvenile rainbow trout following a single iv dose of [3H]4-nonylphenol. Distribution and elimination of [3H]4-nonylphenol residues in tissues sampled 1, 2, 4, 24, 48, 72, and 144 hr after dosing was determined by sample combustion and liquid scintillation counting (LSC). Total 3H-labeled residue concentrations in trout 144 hr after dosing were in order: bile >> faeces >> liver > pyloric caecae > kidney > brain, gill, gonad, heart, plasma, skeletal muscle, and skin. The depletion kinetics of [3H]residues from tissues and plasma was biphasic with prolonged beta-phase half-lives in muscle and liver of 99 hr. Radio-HPLC analysis of metabolites in bile, liver, pyloric caecae, and faeces samples demonstrated similar profiles and contrasted with muscle where only parent compound was found. The predominant metabolite in bile was a glucuronide conjugate of 4-nonylphenol. Other metabolites included glucuronide conjugates of ring or side chain hydroxylated 4-nonylphenol. Liver contained a low level (1.7%) of covalently bound residues. Metabolism studies using isolated trout hepatocytes produced a similar range of metabolites and a sulfate conjugate of hydroxylated 4-nonylphenol. Despite rapid metabolism and excretion, a substantial depot of parent compound remained in muscle which will have implications for the maintenance of 4-nonylphenol residues and associated biological activity.

Title Evaluation of a Recombinant Yeast Cell Estrogen Screening Assay.
Date October 1997
Journal Environmental Health Perspectives

A wide range of chemicals with diverse structures derived from plant and environmental origins are reported to have hormonal activity. The potential for appreciable exposure of humans to such substances prompts the need to develop sensitive screening methods to quantitate and evaluate the risk to the public. Yeast cells transformed with plasmids encoding the human estrogen receptor and an estrogen responsive promoter linked to a reporter gene were evaluated for screening compounds for estrogenic activity. Relative sensitivity to estrogens was evaluated by reference to 17 beta-estradiol (E2) calibration curves derived using the recombinant yeast cells, MCF-7 human breast cancer cells, and a prepubertal mouse uterotrophic bioassay. The recombinant yeast cell bioassay (RCBA) was approximately two and five orders of magnitude more sensitive to E2 than MCF-7 cells and the uterotrophic assay, respectively. The estrogenic potency of 53 chemicals, including steroid hormones, synthetic estrogens, environmental pollutants, and phytoestrogens, was measured using the RCBA. Potency values produced with the RCBA relative to E2 (100) included estrone (9.6), diethylstilbestrol (74.3), tamoxifen (0.0047), alpha-zearalanol (1.3), equol (0.085), 4-nonylphenol (0.005), and butylbenzyl phathalate (0.0004), which were similar to literature values but generally higher than those produced by the uterotrophic assay. Exquisite sensitivity, absence of test compound biotransformation, ease of use, and the possibility of measuring antiestrogenic activity are important attributes that argue for the suitability of the RCBA in screening for potential xenoestrogens to evaluate risk to humans, wildlife, and the environment.

Title Maintenance Therapy with Intravenous Iron in Hemodialysis Patients Receiving Erythropoietin.
Date September 1997
Journal Clinical Nephrology
Title Randomised Controlled Trial of Aspirin and Aspirin Plus Heparin in Pregnant Women with Recurrent Miscarriage Associated with Phospholipid Antibodies (or Antiphospholipid Antibodies)
Date March 1997
Journal Bmj (clinical Research Ed.)

To determine whether treatment with low dose aspirin and heparin leads to a higher rate of live births than that achieved with low dose aspirin alone in women with a history of recurrent miscarriage associated with phospholipid antibodies (or antiphospholipid antibodies), lupus anticoagulant, and cardiolipin antibodies (or anticardiolipin antibodies).

Title Hypophosphatemia in End Stage Renal Disease.
Date January 1997
Journal Nephron

A case of hypophosphatemia in a 55-year-old black female on maintenance hemodialysis is described. She developed multiple bone fractures and congestive heart failure during her 10-year period on hemodialysis. Iliac crest bone biopsy revealed osteomalacia with absent aluminium stores. Management was difficult due to her noncompliance secondary to severe depression. Though osteomalacia and cardiomyopathy due to hypophosphatemia are described in patients with end stage renal disease on dialysis, it is an uncommon entity.

Title Renogastric Fistula Secondary to a Staghorn Calculus.
Date November 1996
Journal The Journal of Urology
Title Subxiphoid Pericardial Window for Pericardial Effusion in End-stage Renal Disease.
Date June 1996
Journal American Journal of Kidney Diseases : the Official Journal of the National Kidney Foundation

Fifty-seven patients with end-stage renal disease who were on maintenance dialysis underwent pericardial fluid drainage surgically between January 1980 and December 1991. All patients had echocardiographically proven pericardial effusion of more than 300 to 500 mL. Seven patients had pericardiectomy by left thoracotomy under general anesthesia in the first 2 years. Subsequently, 50 patients underwent a subxiphoid pericardial window by a left subcostal incision. A pericardial drainage tube was inserted at surgery and removed after 4 to 5 days. All but five patients undergoing subxiphoid pericardial window surgery received local anesthesia. The xiphoid process was not resected during surgery and steroids were not instilled in the pericardial cavity. There were minimal complications, no surgery-related deaths, and no recurrence of fluid in patients after pericardial window surgery. With our present experience, we advise a subxiphoid pericardial window with pericardial drainage under local anesthesia for all end-stage renal disease patients on dialysis who have a symptomatic or large pericardial effusion of more than 300 to 500 mL. Steroid instillation is not necessary for the prevention of recurrence of effusion.

Title Second-trimester Pregnancy Loss is Associated with Activated C Resistance.
Date May 1996
Journal British Journal of Haematology

We have investigated whether activated protein C resistance (APCR) is associated with second-trimester miscarriage. The prevalence of APCR was significantly higher amongst women with a history of second-trimester miscarriage (10/50; 20%) compared with either women with a history of first-trimester miscarriages only (4/70; 5.7%) or a control group of parous women with no previous history of pregnancy losses (3/70; 4.3%) (P < 0.02). These results suggest that APCR may be an important mechanism of second-trimester pregnancy loss, possibly related to the increase in intravascular coagulation that occurs during pregnancy.

Title Antiphospholipid Antibodies and Beta 2-glycoprotein-i in 500 Women with Recurrent Miscarriage: Results of a Comprehensive Screening Approach.
Date March 1996
Journal Human Reproduction (oxford, England)

Five hundred consecutive women (median age 33 years; range 19-45) with a history of recurrent miscarriage (median 4; range 3-16) were screened for the presence of antiphospholipid antibodies (APA)-lupus anticoagulant (LA) and/or anticardiolipin antibodies (ACA). The prevalence of persistently positive tests for LA was 9.6% and for immunoglobulin G (IgG) and immunoglobulin M (IgM) ACA was 3.3 and 2.2% respectively. Only seven women (1.4%) were LA and ACA positive. Repeat testing, after an interval of at least 8 weeks, demonstrated that only 65.7% of LA positive, 36.6% IgG ACA positive and 36.0% IgM ACA positive women on initial testing had a second positive test result. The dilute Russell's viper venom time detected the LA significantly more often than either the activated partial thromboplastin time or the kaolin clotting time (P < 0.001). There was no difference in the gestation of previous miscarriages between APA positive and APA negative women. There was no difference in the plasma beta 2-glycoprotein-I concentrations between APA positive and APA negative women with miscarriages and normal women. All women with a history of recurrent miscarriage should be tested for the presence of both LA and ACA. A second confirmatory test should be performed in those with an initial positive test result.

Title Two Cases of Risperidone-induced Neuroleptic Malignant Syndrome.
Date August 1995
Journal The American Journal of Psychiatry
Title Imidocarb Residues in Edible Bovine Tissues and in Vitro Assessment of Imidocarb Metabolism and Cytotoxicity.
Date August 1995
Journal Drug Metabolism and Disposition: the Biological Fate of Chemicals

Imidocarb residues in liver and muscle were measured by HPLC after a single therapeutic dose to cattle (3 mg imidocarb dipropionate kg-1). Imidocarb and 7-ethoxycoumarin metabolism were compared in three different in vitro systems prepared from bovine liver: cultures of hepatocyte monolayers, precision-cut liver slices, and microsomes. The potential hepatotoxicity of imidocarb residues was tested on hepatocyte monolayers and assessed using the neutral red and lactate dehydrogenase leakage assays. The concentration of imidocarb (mean +/- SD) decreased between days 14 and 224 after treatment from 5.40 +/- 0.61 to 0.12 +/- 0.01 and from 1.05 +/- 0.31 to 0.06 +/- 0.02 microgram g-1 in liver and muscle, respectively. The depletion kinetics of imidocarb fitted a two-compartment model with alpha- and beta-phase half-lives of 31.7 and 48.5 days in liver and 34.9 and 120.7 days in muscle, respectively. Imidocarb metabolites were not detected in any in vitro system. 7-Ethoxycoumarin metabolism was found in all in vitro systems; the predominant metabolite produced by hepatocyte and liver slice cultures was umbelliferone glucuronide. Cytotoxicity of imidocarb (100 microM) to hepatocyte monolayers was maximal after 72 hr treatment and dose-dependent above 10 microM imidocarb. It is most likely that the hepatotoxicity of imidocarb is caused by the parent compound, because no evidence for imidocarb metabolism was found.

Title Hypoglycaemic--hemiplegia.
Date March 1995
Journal The Journal of the Association of Physicians of India
Title Nadolol for Lithium Tremor in the Presence of Liver Damage.
Date November 1994
Journal Annals of Clinical Psychiatry : Official Journal of the American Academy of Clinical Psychiatrists

Lithium-induced tremor classically responds to treatment with propranolol. Since it is metabolized in the liver, propranolol may not be the drug of choice in those patients who have compromised liver function or who are recovering from prior liver diseases. Another nonselective beta-adrenergic blocker, nadolol, has no hepatic biotransformation. We present here the first case report of successful treatment of lithium-induced tremor with nadolol, which was selected because the patient had compromised liver function. The patient's liver function tests remained stable with the therapy.

Title Tardive Oculogyric Crises with Clozapine.
Date September 1994
Journal The Journal of Clinical Psychiatry
Title Fluoxetine-associated Dystonia.
Date January 1994
Journal The American Journal of Psychiatry
Title Pharmacodynamics of Zidovudine in Patients with End-stage Renal Disease.
Date March 1992
Journal The New England Journal of Medicine
Title Depression in Alcoholics: Implications for Treatment.
Date July 1985
Journal Jama : the Journal of the American Medical Association
Title Thiocyanate As a Marker of Saliva in Gastric Juice?
Date June 1980
Journal Gut

One source of error in gastric secretion studies is swallowed saliva. The possibility that salivary thiocyanate might be used to measure this contamination has been investigated. Thiocyanate concentration was measured in saliva and gastric juice collected simultaneously in 22 duodenal ulcer patients undergoing routine insulin and histamine secretion studies. On stimulation, despite the increase in the rate of gastric secretion this was not matched by an appropriate fall in the concentration of thiocyanate in gastric juice. Moreover, in one-third of the gastric juice specimens, the thiocyanate concentration was greater than in the simultaneous samples of saliva. Thus, contrary to what has been claimed, thiocyanate is present not only in saliva but also in gastric juice. Therefore it cannot be used as a marker of salivary contamination. An adequate marker of this source of error has not yet been found.

Title Some Cardiovascular Actions of Sodium Tauroglycocholate.
Date December 1974
Journal Indian Journal of Physiology and Pharmacology
Title Further Studies on the Sympathomimetic Action of Tetanus Toxin.
Date September 1971
Journal Japanese Journal of Pharmacology
Title The Antioxidant Resveratrol Protects Against Chondrocyte Apoptosis Via Effects on Mitochondrial Polarization and Atp Production.
Journal Arthritis and Rheumatism

OBJECTIVE: To determine the effects of the antioxidant resveratrol on the functions of human chondrocytes in osteoarthritis (OA). METHODS: Chondrocytes and cartilage explants were isolated from OA patients undergoing knee replacement surgery. Effects of resveratrol in the presence or absence of interleukin-1beta (IL-1beta) stimulation were assessed by measurement of prostaglandin E(2) (PGE(2)) and leukotriene B(4) (LTB(4)) synthesis, cyclooxygenase (COX) activity, matrix metalloproteinase (MMP) expression, and proteoglycan production. To explore the mechanisms of action of resveratrol, its effects on mitochondrial function and apoptosis were examined by assessing mitochondrial membrane potential, ATP levels, cytochrome c release, and annexin V staining. RESULTS: Resveratrol inhibited both spontaneous and IL-1beta-induced PGE(2) production by >20% (P < 0.05) and by 80% (P < 0.001), respectively; similarly, LTB(4) production was reduced by >50% (P < 0.05). The production of PGE(2) was inhibited via a 70-90% suppression of COX-2 expression and enzyme activity (P < 0.05). Resveratrol also promoted anabolic effects in OA explant cultures, by elevating proteoglycan synthesis and decreasing production of MMPs 1, 3, and 13. Pretreatment of OA chondrocytes with resveratrol blocked mitochondrial membrane depolarization, loss of mitochondrial biomass, and IL-1beta-induced ATP depletion. Similarly, IL-1beta-mediated induction of the apoptotic markers cytochrome c and annexin V was also inhibited by resveratrol. Exogenous addition of PGE(2) abolished the protective effects of resveratrol on mitochondrial membrane integrity, ATP levels, expression of apoptotic markers, and DNA fragmentation. CONCLUSION: Resveratrol protects against IL-1beta-induced catabolic effects and prevents chondrocyte apoptosis via its inhibition of mitochondrial membrane depolarization and ATP depletion. These beneficial effects of resveratrol are due, in part, to its capacity to inhibit COX-2-derived PGE(2) synthesis. Resveratrol may therefore protect against oxidant injury and apoptosis, which are main features of progressive OA.

Title F-spondin, a Neuroregulatory Protein, is Up-regulated in Osteoarthritis and Regulates Cartilage Metabolism Via Tgf-{beta} Activation.
Journal The Faseb Journal : Official Publication of the Federation of American Societies for Experimental Biology

In osteoarthritis (OA) articular chondrocytes undergo phenotypic changes culminating in the progressive loss of cartilage from the joint surface. The molecular mechanisms underlying these changes are poorly understood. Here we report enhanced ( approximately 7-fold) expression of F-spondin, a neuronal extracellular matrix glycoprotein, in human OA cartilage (P<0.005). OA-specific up-regulation of F-spondin was also demonstrated in rat knee cartilage following surgical menisectomy. F-spondin treatment of OA cartilage explants caused a 2-fold increase in levels of the active form of TGF-beta1 (P<0.01) and a 10-fold induction of PGE2 (P<0.005) in culture supernatants. PGE2 induction was found to be dependent on TGF-beta and the thrombospondin domain of the F-spondin molecule. F-spondin addition to cartilage explant cultures also caused a 4-fold increase in collagen degradation (P<0.05) and a modest reduction in proteoglycan synthesis ( approximately 20%; P<0.05), which were both TGF-beta and PGE2 dependent. F-spondin treatment also led to increased secretion and activation of MMP-13 (P<0.05). Together these studies identify F-spondin as a novel protein in OA cartilage, where it may act in situ at lesional areas to activate latent TGF-beta and induce cartilage degradation via pathways that involve production of PGE2.-Attur, M. G., Palmer, G. D., Al-Mussawir, H. E., Dave, M., Teixeira, C. C., Rifkin, D. B., Appleton, C. T. G., Beier, F., Abramson, S. B. F-spondin, a neuroregulatory protein, is up-regulated in osteoarthritis and regulates cartilage metabolism via TGF-beta activation.

Title Prostaglandin E2 Exerts Catabolic Effects in Osteoarthritis Cartilage: Evidence for Signaling Via the Ep4 Receptor.
Journal Journal of Immunology (baltimore, Md. : 1950)

Elevated levels of PGE(2) have been reported in synovial fluid and cartilage from patients with osteoarthritis (OA). However, the functions of PGE(2) in cartilage metabolism have not previously been studied in detail. To do so, we cultured cartilage explants, obtained from patients undergoing knee replacement surgery for advanced OA, with PGE(2) (0.1-10 muM). PGE(2) inhibited proteoglycan synthesis in a dose-dependent manner (maximum 25% inhibition (p < 0.01)). PGE(2) also induced collagen degradation, in a manner inhibitable by the matrix metalloproteinase (MMP) inhibitor ilomastat. PGE(2) inhibited spontaneous MMP-1, but augmented MMP-13 secretion by OA cartilage explant cultures. PCR analysis of OA chondrocytes treated with PGE(2) with or without IL-1 revealed that IL-1-induced MMP-13 expression was augmented by PGE(2) and significantly inhibited by the cycolooygenase 2 selective inhibitor celecoxib. Conversely, MMP-1 expression was inhibited by PGE(2), while celecoxib enhanced both spontaneous and IL-1-induced expression. IL-1 induction of aggrecanase 5 (ADAMTS-5), but not ADAMTS-4, was also enhanced by PGE(2) (10 muM) and reversed by celecoxib (2 muM). Quantitative PCR screening of nondiseased and end-stage human knee OA articular cartilage specimens revealed that the PGE(2) receptor EP4 was up-regulated in OA cartilage. Moreover, blocking the EP4 receptor (EP4 antagonist, AH23848) mimicked celecoxib by inhibiting MMP-13, ADAMST-5 expression, and proteoglycan degradation. These results suggest that PGE(2) inhibits proteoglycan synthesis and stimulates matrix degradation in OA chondrocytes via the EP4 receptor. Targeting EP4, rather than cyclooxygenase 2, could represent a future strategy for OA disease modification.

Title Personalizing Stem Cell Research and Therapy: The Arduous Road Ahead or Missed Opportunity?
Journal Current Pharmacogenomics and Personalized Medicine

The euphoria of stem cell therapy has diminished, allowing scientists, clinicians and the general public to seriously re-examine how and what types of stem cells would effectively repair damaged tissue, prevent further tissue damage and/or replace lost cells. Importantly, there is a growing recognition that there are substantial person-to-person differences in the outcome of stem cell therapy. Even though the small molecule pharmaceuticals have long remained a primary focus of the personalized medicine research, individualized or targeted use of stem cells to suit a particular individual could help forecast potential failures of the therapy or identify, early on, the individuals who might benefit from stem cell interventions. This would however demand collaboration among several specialties such as pharmacology, immunology, genomics and transplantation medicine. Such transdisciplinary work could also inform how best to achieve efficient and predictable stem cell migration to sites of tissue damage, thereby facilitating tissue repair. This paper discusses the possibility of polarizing immune responses to rationalize and individualize therapy with stem cell interventions, since generalized "one-size-fits-all" therapy is difficult to achieve in the face of the diverse complexities posed by stem cell biology. We also present the challenges to stem cell delivery in the context of the host related factors. Although we focus on the mesenchymal stem cells in this paper, the overarching rationale can be extrapolated to other types of stem cells as well. Hence, the broader purpose of this paper is to initiate a dialogue within the personalized medicine community by expanding the scope of inquiry in the field from pharmaceuticals to stem cells and related cell-based health interventions.

Title [intraosseous Infusion in the Pediatric Emergency Medical Service : Analysis of Emergency Medical Missions 1990-2009.]
Journal Der Anaesthesist

BACKGROUND: Timely establishment of venous access in infants and toddlers during emergency medical care can be a particularly challenging task. Alternative routes for drug and fluid administration, such as endobronchial, intramuscular, central venous or venous cut-down do not offer reliable solutions. Intraosseous infusion (IOI) has become established as an effective alternative intravascular access for rapid and efficient drug delivery. IOI was introduced in our local emergency medical service (EMS) in 1993 and was assigned a high priority in international guidelines for pediatric emergency medical care in 2000 and 2005. The aim of this study was to review the impact of the introduction of IOI on drug administration routes during prehospital emergency treatment of critically ill or severely injured pediatric patients (NACA index V-VII) in our tertiary medical care centre over a period of 20 years. METHODS: Pediatric prehospital emergency medical protocols from 1990 to 2009 were analyzed with respect to the administration routes for fluids and medications in severely injured or critically ill children with NACA severity scores V-VII. The frequency and mode of vascular access during prehospital treatment including IOI, endobronchial administration, central venous catheterization (CVC) and intramuscular administration as well as prehospital treatment and transportation without vascular access were analyzed. Two groups were compared: the introduction phase of IOI between 1990 and 1999 and the phase of growing IOI routine after introducing guidelines and regular staff IOI technique training between 2000 and 2009. Demographic data and drug administration routes in the two different time periods were analyzed using the Mann-Whitney-u test and t-test or χ(2)-test, respectively. A p-value <0.05 was regarded as significant. RESULTS: A total of 5,279 pediatric prehospital emergency charts were analyzed and 401 patients (7.6%) were scored as NACA V-VII. At the emergency scene 299 patients (75%) received a peripheral intravenous access, 3 (0.7%) a central venous line access, 77 (19%) an intraosseous needle and in 22 (5.4%) no vascular or intraosseous access was used during the course of prehospital treatment (NACA VII - 13 patients, NACA VI - 2 patients, NACA V - 7 patients). Of the NACA VII patients 3 were transported under continuous cardiopulmonary resuscitation without vascular access. After 2002 all patients with NACA index VII were treated with vascular or intraosseous access. In 48 patients (12%) at least initial medication was given by the endobronchial or alternative route but within the last 3 years endobronchial drug administration was no longer reported. Thus, in 124 critically ill patients (31%) routine peripheral venous access could not be established initially or until the end of treatment (77 times IOI, 22 times no access over the course of treatment, 3 times CVC and 22 times initial endobronchial followed by peripheral venous access). Over the reviewed period the use of IOI increased significantly (p<0.001), while the incidence of lacking vascular access (p<0.05) and alternative drug administration routes (p<0.001) continuously decreased. CONCLUSION: The IOI technique has not only been assigned a high priority in the guidelines for pediatric emergency care of critically ill children with difficult or failed venous access but has also significantly influenced current prehospital care. The introduction of the IOI technique in our prehospital pediatric emergency system has markedly reduced the number of critically ill or severely injured pediatric patients without vascular access or with less reliable alternative administration routes in the last 20 years.

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