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Biomedical subjects

R Paul

Publications and source records attributed to R Paul.

At least 91 records · Page 5Linked to original sources
PubMed1998

Cognitive efficiency in alcoholics and polysubstance abusers.

Previous studies have found alcoholics to be impaired on tests of cognitive efficiency. However, it is unclear to what extent individuals who abuse drugs in addition to alcohol exhibit similar deficits. To answer this question, 63 healthy control subjects were compared with 40 individuals who abused alcohol only, 24 individuals who abused alcohol and stimulants, 16 individuals who abused alcohol and marijuana, and 41 individuals who abused alcohol and depressants/narcotics, or alcohol and two or more other drugs. All subjects were administered tests of short-term memory, spatial orientation, visual-spatial perception, and problem-solving. Results from the study indicated that control subjects and individuals who abused both alcohol and marijuana performed significantly better than the other groups on most tests. These results were not attributable to differences on measures of affect or chronicity of alcohol consumption.

Adult↗
PubMed1998

Ets-1 is an early response gene activated by ET-1 and PDGF-BB in vascular smooth muscle cells.

Ets-1 is a transcription factor that activates expression of matrix-degrading proteinases such as collagenase and stromelysin. To study the control of ets-1 gene expression in rat vascular smooth muscle cells (VSMC), cells were exposed to factors known to regulate VSMC migration and proliferation. Platelet-derived growth factor-BB (PDGF-BB), endothelin-1 (ET-1), and phorbol 12-myristate 13-acetate (PMA) induced a dose-dependent expression of ets-1 mRNA. These effects were abrogated by inhibition of protein kinase C (PKC) by H-7 or chronic PMA treatment. Ets-1 mRNA was superinduced by PDGF-BB and ET-1 in the presence of cycloheximide. The chelation of intracellular Ca2+ by 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid-acetoxymethyl ester and the depletion of endoplasmic reticulum intracellular Ca2+ concentration ([Ca2+]i) by thapsigargin inhibited PDGF-BB- and ET-1-induced ets-1 mRNA, whereas ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid had no effect. However, [Ca2+]i release alone was not sufficient to increase ets-1 mRNA. Forskolin blocked ET-1-, PDGF-BB-, and PMA-induced ets-1 mRNA, as well as inositol phosphate formation, consistent with an effect through impairment of PKC activation. Inhibitors of ets-1 gene expression, such as H-7 and herbimycin A, inhibited the ET-1 induction of collagenase I mRNA. We propose that ets-1 may be an important element in the orchestration of matrix proteinase expression and of vascular remodeling after arterial injury.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1998

Both the immunosuppressant SR31747 and the antiestrogen tamoxifen bind to an emopamil-insensitive site of mammalian Delta8-Delta7 sterol isomerase.

SR31747 is a novel agent that elicits immunosuppressive and anti-inflammatory effects. This drug was shown to inhibit Delta8-Delta7 sterol isomerase in yeast. To test whether this enzyme could also be an SR31747 target in mammals, the binding, antiproliferative and sterol biosynthesis inhibitory properties of various drugs were studied in recombinant sterol isomerase-producing yeast cells. Our results clearly show that SR31747 is a high affinity ligand of recombinant mammalian sterol isomerase (Kd = 1 nM). Tridemorph, a sterol biosynthesis inhibitor that is widely used in agriculture as an antifungal agent, is also a powerful inhibitor of murine and human sterol isomerases (IC50 value in the nanomolar range). Some drugs, like cis-flupentixol, trifluoperazine, 7-ketocholestanol and tamoxifen, inhibit SR31747 binding only with the mammalian enzymes, whereas other drugs, like haloperidol and fenpropimorph, are much more effective with the yeast enzyme than with the mammalian ones. Emopamil, a high affinity ligand of human sterol isomerase, is inefficient in inhibiting SR31747 binding to its mammalian target, suggesting that the SR31747 and emopamil binding sites on mammalian sterol isomerase do not overlap. In contrast, SR31747 binding inhibition by tamoxifen is very efficient and competitive (IC50 value in the nanomolar range), indicating that mammalian sterol isomerase contains a so-called antiestrogen binding site. Tamoxifen is found to selectively inhibit sterol biosynthesis at the sterol isomerase step in the cells that are producing the mammalian enzyme in place of their own sterol isomerase. Finally, we also show that tridemorph, a sterol biosynthesis inhibitor widely used in agriculture as an antifungal agent, is not selective of yeast Delta8-Delta7 sterol isomerase but is also highly efficient against murine Delta8-Delta7 sterol isomerase or human Delta8-Delta7 sterol isomerase. This observation contrasts with our already published results showing that fenpropimorph, another sterol isomerase inhibitor used in agriculture, is only poorly efficient against the mammalian enzymes.

Animals↗
PubMed1998

In vitro thrombogenicity testing of artificial organs.

Thromboembolic complications remain as one of the main problems for blood contacting artificial organs such as heart valves, bloodpumps and others. In vitro evaluation of thrombogenesis in prototypes has not previously been part of the standard evaluation of these devices. In comparison to hemolysis testing, evaluation of the thrombogenic potential is more difficult to perform because of the complexity of the blood coagulation system. We present an in vitro testing procedure that allows the accelerated examination of the thrombogenic potential of different types of blood pumps. Additionally, first results are presented that indicate the reliability of the accelerated clotting test for mechanical heart valves. Results for the centrifugal pump BioMedicus and two microaxial pumps have shown typical thrombus formation at locations such as bearings. The results indicate that the accelerated clotting test is an excellent addition to the much more expensive animal testing of artificial organs or assist devices. In vitro testing permits studies of thrombus formation to be performed at an early stage and at low costs and also facilitates a more precise investigation of device areas known to be potential hot spots for thrombus formation.

Animals↗
PubMed1997

Purification and characterization of the human SR 31747A-binding protein. A nuclear membrane protein related to yeast sterol isomerase.

SR 31747A, defined as a sigma ligand, is a novel immunosuppressive agent that blocks proliferation of human and mouse lymphocytes. Using a radiolabeled chemical probe, we here purified a target of SR 31747A and called it SR 31747A-binding protein (SR-BP). Purified SR-BP retained its binding properties and migrated on SDS-polyacrylamide gel as a Mr 28,000 protein. Cloning of the cDNA encoding human SR-BP shows an open reading frame for a 223-amino acid protein, which is homologous to the recently cloned sigma 1 receptor. Interestingly, the deduced amino acid sequence was found to be related to fungal C8-C7 sterol isomerase, encoded by the ERG2 gene. The ERG2 gene product has been identified recently as the molecular target of SR 31747A that mediates antiproliferative effects of the drug in yeast. Northern blot analysis of SR-BP gene expression revealed a single transcript of 2 kilobases which was widely expressed among organs, with the highest abundance in liver and the lowest abundance in brain. Subcellular localization analysis in various cells, using a specific monoclonal antibody raised against SR-BP, demonstrated that this protein was associated with the nuclear envelope. When studying the binding of SR 31747A on membranes from yeast expressing SR-BP, we found a pharmacological profile of sigma 1 receptors; binding was displaced by (+)-pentazocine, haloperidol, and (+)-SKF 10,047, with (+)-SKF 10, 047 being a more potent competitor than (-)-SKF 10,047. Scatchard plot analysis revealed Kd values of 7.1 nM and 0.15 nM for (+)-pentazocine and SR 31747A, respectively, indicating an affinity of SR-BP 50-fold higher for SR 31747A than for pentazocine. Additionally, we showed that pentazocine, a competitive inhibitor of SR 31747A binding, also prevents the immunosuppressive effect of SR 31747A. Taken together, these findings strongly suggest that SR-BP represents the molecular target for SR 31747A in mammalian tissues, which could be critical for T cell proliferation.

Amino Acid Sequence↗
PubMed1997

Theory of Electrode Polarization in Dielectrophoresis and Electrorotation

Experimental observations, previously reported in the low frequency regime of the spectrum in dielectrophoresis and electrorotation of plant protoplasts, have revealed serious discrepancies between the predictions of the "Shelled Model" and measurements. Much work has also been carried out in the theoretical realm to reconcile these discrepancies by introducing such mechanisms as charge flow on the surface of the cell and micromotion, but in all this the effects of electrode polarization have been neglected. Part of the problem lies in the rather formidable nature of the analysis that must be carried out with nonuniform fields since the entire system of governing partial differential equations must be considered. In the case of uniform fields it is convenient to formulate the problem in the language of ordinary differential equations. This problem is further exacerbated by the lack of a well defined boundary condition at the outer limit of the double layer. We have used the method of Green's functions, since this allows the consideration of partial differential equations in a more natural way than the other methods, in order to formulate the problem. The lack of a well defined boundary condition at the outer surface is dealt with by taking an integral transform of the governing equations and thus recovering a relationship between the applied and the far fields. The results of our analysis show that the double layer relaxation, in the selected model, is a very simple single relaxation process and its effect is to diminish the discrepancies between theory and experiment. Copyright 1997 Academic Press. Copyright 1997Academic Press

Journal Article↗
PubMed1997

Theory of Electrode Polarization in Dielectrophoresis and Electrorotation

The analysis begun in the previous paper on the role of electrode polarization in experimental measurements using dielectrophoresis and electrorotation in a polar spherical coordinate frame is extended to include other curvilinear coordinate systems. The Green functions, as derived in the previous paper in terms of the Dyson equation, is shown to obey a variational theorem that allows the inclusion of the equilibrium potential and the Stern layer effect neglected thus far. Copyright 1997 Academic Press. Copyright 1997Academic Press

Journal Article↗
PubMed1997

Cloning and expression analysis of a meiosis-specific MutS homolog: the human MSH4 gene.

The Escherichia coli MutHLS system has been highly conserved throughout evolution. The eukaryotic pathway results in a specialization of MutS homologs that have evolved to play crucial roles in both DNA mismatch repair and meiotic recombination. So far, meiosis-specific genes belonging to this family have only been identified in yeast. In Saccharomyces cerevisiae, MSH4 (MutS homolog 4) is a meiosis-specific protein that is not involved in mismatch correction. This protein is required for reciprocal recombination and proper segregation of homologous chromosomes at meiosis I. We have identified the human MSH4 homolog gene. The predicted amino acid sequence shows 28.7% identity with the S. cerevisiae MSH4 protein. By Northern blot analysis, human MSH4 transcripts are only detectable in testis and in ovary with a lower level of expression. We have mapped MSH4 to human chromosome 1 at band p31 by fluorescence in situ hybridization. The identification of such a gene provides a powerful tool for clarifying the respective roles of MSH and MLH genes in mammalian meiosis.

Adenosine Triphosphatases↗
PubMed1997

Cadherin-6, a cell adhesion molecule specifically expressed in the proximal renal tubule and renal cell carcinoma.

Cadherins are a family of calcium-dependent, cell-cell adhesion molecules that play an important morphoregulatory role in a wide variety of tissues. Alterations in cadherin function have been implicated in tumor progression in a number of adenocarcinomas. Despite the increasing number of new cadherins identified, little is known about cadherins in normal renal tissue and renal carcinomas. A novel cadherin transcript, cadherin-6, was recently described to be present in renal cancer cell lines and fetal kidney, but no data on protein expression nor tissue localization has been reported. In this study, we demonstrate that the expression of cadherin-6 is restricted to the proximal tubule epithelium. This finding is critical because these cells give rise to the majority of neoplasms of this organ. Furthermore we demonstrate typical cadherin features of cadherin-6, including cytoplasmic binding to alpha- and beta-catenin. We present data of cadherin-6 expression in a series of 32 primary renal cell cancers. Cadherin-6 expression tended to vary with histology in these samples. Whereas the majority of renal cell cancers with histology-associated poor prognosis (i.e., high grade clear cell carcinomas and sarcomatoid renal tumors) show aberrant expression of cadherin-6, in tumors with a favorable prognosis (i.e., low grade clear cell carcinomas and papillary cancers), normal cadherin-6 expression was predominant. Overall, these findings demonstrate specific expression of cadherin-6 in the proximal renal tubules in normal human kidney and suggest that alterations of cadherin-6 expression are associated with progression of renal cell carcinoma.

Cadherins↗
PubMed1997

Iridium 192 high-dose-rate brachytherapy--a useful alternative therapy for localized prostate cancer?

We report on a novel protocol involving iridium 192 high-dose-rate brachytherapy and follow-up of up to 130 months in patients with prostatic carcinoma. Using regional anesthesia, five to seven hollow needles are placed within the prostate by perineal puncture under ultrasound guidance. A 9-Gy prostate dose is applied followed by 30 min of hyperthermia (since 1991). This treatment is repeated once after 7 days; 2 weeks later, 18 x 2-Gy external beam radiation (small-field prostate) is added as percutaneous dose saturation. Since 1984 we have treated 40 patients with this protocol. Local tumor control was achieved by means of prostatic biopsy at 18 months after therapy and determination of prostate-specific antigen (PSA) values in about 70% of the patients; after a mean follow-up period of more than 6 years (16-130 months), 80% of the patients show either no evidence of disease or stable disease. We therefore conclude that iridium 192 high-dose-rate brachytherapy is a useful alternative in the treatment of localized prostate cancer in patients who are not eligible for radical prostatectomy.

Adult↗
PubMed1997

Leptospirosis in Kolenchery, Kerala, India: epidemiology, prevalent local serogroups and serovars and a new serovar.

Leptospirosis is the most widespread zoonosis in the world. It is mostly an occupational disease especially in rural areas. Kolenchery is in the midlands of Kerala. The landscape consists of marshy land and dry land interspersed by rivulets and ponds. Irrigation of dry lands for cultivation during the summer months started in mid 1980s after the irrigation projects were commissioned. Cases of leptospirosis were rarely diagnosed in Kolenchery before 1987. Since then a yearly increase in incidence is observed. No major study on either epidemiology or clinical picture has been done on human leptospirosis in Kerala so far. The aim of this study was to define the major clinical presentations, epidemiology of the infection and demonstrate the predominant serogroups and serovars causing the illness in this limited geographical area. The study involves 976 cases of leptospirosis confirmed by culture and/or serological tests. Serogroups Autumnalis, Australis and Icterohaemorrhagiae were the commonest. Mortality rate was 5.32%. The increase in incidence is probably due to the geographical characteristics, continuous moisture of the soil due to irrigation in summer and year-round cultivation making food and cover available to host rodents. Close interaction of humans, animals, soil and water in this region make the spread of leptospirosis to humans easy. Confirmation of cases has been done by enzyme linked immunosorbent assay (ELISA) and/or microscopic agglutination test (MAT) and/or by culture. Serovar identification has been done in 21 cultures isolated from patients. One new serovar belonging to serogroup Australis has been identified from a patient and named serovar Australis bharathy.

Adolescent↗
PubMed1997

Reading and metaphonological outcomes in late talkers.

Children with a history of slow expressive language development (SELD) were followed to second grade, at which point outcomes in terms of speech, language, cognitive skills, reading achievement, and metaphonological performance were evaluated. Although there were some statistically significant differences between groups, children with a history of SELD generally performed within the normal range on the measures collected. Relations among speech, reading, and metaphonology in the SELD cohort appeared to operate in a manner similar to that seen in groups with typical language development. The implications of these findings for understanding the nature of specific language impairments and for treating early circumscribed language delays are discussed.

Achievement↗
PubMed1997

7-Nitroindazole inhibits pial arteriolar vasodilation in a rat model of pneumococcal meningitis.

This study investigates how the neuronal and inducible nitric oxide synthase (NOS) pathways contribute to the cerebrovascular changes in the early phase of experimental pneumococcal meningitis in rats. Using a closed cranial window preparation, the diameters of pial arterioles were measured during 4 hours after intracisternal injection of heat-killed pneumococci and compared with controls (n = 6). Injection of pneumococci (n = 7) caused a significant increase in pial arteriolar diameter (157 +/- 22% after 4 hours; P < 0.05, compared with 104 +/- 11% in controls), intracranial pressure, CSF white blood cell counts, and brain water content. Treatment with the neuronal NOS inhibitor 7-nitroindazole (50 mg/kg given intraperitoneally, n = 5) prevented pneumococci-induced vasodilation (107 +/- 20% at 4 hours), whereas S-methylisothiourea (SMT; 0.1 mg/kg given intraperitoneally, n = 5), which predominantly inhibits the inducible NOS, did not influence pneumococci-induced vasodilation (154 +/- 38% at 4 hours). S-methylisothiourea at a dose of 1.0 mg/kg (n = 5), attenuated the vasodilation (124 +/- 18% at 4 hours). However, the increase in mean arterial blood pressure after SMT at 1.0 mg/kg, but not at 0.1 mg/kg, suggests that the higher dose of SMT influenced the constitutive NOS activity, causing inhibition of the pneumococci-induced vasodilation. Neither SMT (at both doses) nor 7-nitroindazole influenced the increase in brain water content, intracranial pressure, and CSF white blood cell counts in pneumococci-challenged rats. Our study suggests that pial arteriolar vasodilation in the early phase of experimental pneumococcal meningitis is mediated by the neuronal NOS pathway.

Animals↗
PubMed1997

The cadherin cell-cell adhesion pathway in prostate cancer progression.

Cadherins are a family of calcium-dependent cell-cell adhesion molecules involved in cell-cell aggregation and morphoregulatory cell function. Dysfunction of the cadherin pathway is involved in tumour invasiveness and disease progression for a variety of carcinomas. E-cadherin is a prognostic marker in prostatic cancer, based on the correlation of the grade of E-cadherin expression and tumour grade, stage, metastasis and survival, as well as recurrence after radical prostatectomy. P-cadherin was shown to be lost in all prostatic cancers, although this most likely reflects loss of the basal cell population rather than a transcriptional down-regulation, suggesting that loss of P-cadherin expression is an early event in the tumorigenesis of prostatic carcinomas. Catenins, particularly alpha-catenin, also play an important role in the dysfunction of the cell adhesion complex. Mechanisms of inactivation of the cadherin-catenin pathway include LOH, gene deletions and gene promoter hypermethylation. Therapeutic strategies have been investigated in tumour models, i.e. the use of demethylating agents for the hypermethylated promoter region of E-cadherin or gene transfer in PC-3 cells with homozygous deletion of the alpha-catenin gene. The complexity of neoplastic changes cannot be explained by alterations of cell adhesion molecules alone; but as demonstrated, cadherins and catenins play an important role in this process.

Cadherins↗
PubMed1997

Temperament in late talkers.

This study examines the temperamental characteristics of children who were identified at age two as being slow in expressive language development, and those of peers with normal language history. When the children were in first grade (approximately age six), parents and clinicians rated subjects' temperamental characteristics, using a standardized temperament assessment instrument. Subjects with a history of slow expressive language development were rated significantly lower on Approach/Withdrawal--indicating shyness, aloofness, or reduced outgoingness--than peers with normal language history. Approach/Withdrawal scores were significantly correlated with average sentence length in spontaneous speech, and this measure also predicted Approach/Withdrawal scores in regression analyses. The clinical and theoretical implications of these findings for early language delay are discussed.

Child↗
PubMed1997

Severe antibody-mediated human insulin resistance: successful treatment with the insulin analog lispro. A case report.

OBJECTIVE: To evaluate the efficacy of the insulin analog lispro (Lys B28, Pro B29) in severe insulin resistance caused by human insulin antibodies. CASE: A 27-year-old man with a history of diabetes treated with human insulin for 3 years developed severe immunological insulin resistance caused by human insulin antibodies. Throughout follow-up (12 months) the insulin analog lispro was administered with an infusion pump as the only insulin therapy. The insulin dose decreased from an average of 300 U/day to 58 U/day, HbA1c decreased from 12.6 to 7.4%, and human insulin antibodies decreased from 8,057 to 1,860 nU/ml. Hypoglycemic episodes during early morning disappeared. CONCLUSIONS: The insulin analog lispro might be suitable for the treatment of diabetic patients with substantially increased insulin antibody levels Apparently, the structural difference between the lispro and human insulin molecules prevented lispro from binding to the human insulin antibodies in this patient and consequently was nonimmunogenic.

Adult↗