Kidney transplantation in France.
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France↗
Biomedical subjects
S Cohen
Publications and source records attributed to S Cohen.
Treatment of active rheumatoid arthritis with leflunomide compared with placebo and methotrexate. Leflunomide Rheumatoid Arthritis Investigators Group.
CONTEXT: Leflunomide is a reversible inhibitor of de novo pyrimidine synthesis shown to be effective in a phase 2 trial in 402 patients with active rheumatoid arthritis (RA). OBJECTIVE: To compare the efficacy and safety of leflunomide treatment with placebo and methotrexate treatment in patients with active RA. DESIGN: Randomized, double-blind, placebo, and active-controlled 12-month study. SETTING: Forty-seven university and private rheumatology practices in the United States and Canada. PATIENTS: Diagnosis of RA by the American College of Rheumatology (ACR) criteria for duration of 6 months or longer and no previous methotrexate treatment. INTERVENTION: Leflunomide treatment (20 mg/d), placebo, or methotrexate treatment (7.5-15 mg/wk). MAIN OUTCOME MEASURES: American College of Rheumatology success rate (completed 52 weeks of treatment and met the ACR > or = 20% response criteria), disease progression as assessed by x-ray films, and improvement in function and health-related quality of life using the intent-to-treat population. RESULTS: The 482 patients studied were predominantly women (mean age, 54 years; mean disease duration, 6.7 years) for whom a mean of 0.8 disease-modifying antirheumatic drugs had failed. The ACR response and success rates for patients receiving leflunomide treatment (52% and 41%, respectively) and methotrexate treatment (46% and 35%, respectively) were significantly higher than those for patients receiving placebo (26% and 19%, respectively) (P<.001), and they were statistically equivalent, with mean time to initial response at 8.4 weeks for patients receiving leflunomide vs 9.5 weeks for patients receiving methotrexate therapy. X-ray analyses demonstrated less disease progression with leflunomide (P=.001) and methotrexate (P = .02) therapy than with placebo. Leflunomide and methotrexate treatment improved measures of physical function and health-related quality of life significantly more than placebo (P<.001 and P<.05, respectively). Common adverse events for patients receiving leflunomide treatment included gastrointestinal complaints, skin rash, and reversible alopecia. Asymptomatic transaminase elevations resulted in treatment discontinuations for 7.1% of patients receiving leflunomide therapy, 1.7% of patients receiving placebo, and 3.3% of patients receiving methotrexate therapy. CONCLUSIONS: Clinical responses following administration of leflunomide, a new therapeutic agent for the treatment of RA, were statistically superior to those with placebo and equivalent to those with methotrexate treatment. Both active treatments improved signs and symptoms of active RA, delayed disease progression as demonstrated by x-ray films, and improved function and health-related quality of life.
Adult↗
Annexin VII and annexin XI are tyrosine phosphorylated in peroxovanadate-treated dogs and in platelet-derived growth factor-treated rat vascular smooth muscle cells.
The intraperitoneal administration of peroxovanadate results in the rapid accumulation of many tyrosine-phosphorylated proteins in the liver and kidney of treated animals. The availability of large pools of tyrosine-phosphorylated proteins derived from normal tissues facilitates the purification and identification of previously unknown targets for cellular tyrosine kinases. Using this procedure, we have thus far identified four proteins in the liver and kidney of peroxovanadate-treated dogs. Two of these, annexin VII and annexin XI, were novel and had not been previously reported to be substrates of tyrosine kinases while the remaining two, ezrin and clathrin, have been reported to be tyrosine phosphorylated in some cell culture systems. In the present study, isolated proteins were identified both by sequence analysis and immunological methods. Annexin VII and annexin XI are present in cultured rat vascular smooth muscle cells and both were tyrosine phosphorylated in response to a physiological ligand, platelet-derived growth factor-BB (PDGF-BB). Furthermore, the extent of tyrosine phosphorylation in response to PDGF-BB was augmented by the co-addition of peroxovanadate to cell cultures. In vitro phosphorylation assays showed that PDGF receptor, calcium-dependent tyrosine kinase (CADTK/Pyk-2), Src kinase, and epidermal growth factor receptor all were able to phosphorylate purified annexin VII and XI on tyrosine residues. These findings confirm the usefulness of phosphatase inhibition by peroxovanadate as a tool for identifying previously unknown physiological targets for cellular protein tyrosine kinases.
Amino Acid Sequence↗
ABC of intensive care. Withdrawal of treatment.
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Critical Care↗
Heartburn--a serious symptom.
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Adenocarcinoma↗
Cloning and characterization of a lymphoid-specific, inducible human protein tyrosine phosphatase, Lyp.
Protein tyrosine phosphatases act in conjunction with protein kinases to regulate the tyrosine phosphorylation events that control cell activation and differentiation. We have isolated a previously undescribed human phosphatase, Lyp, that encodes an intracellular 105-kD protein containing a single tyrosine phosphatase catalytic domain. The noncatalytic domain contains four proline-rich potential SH3 domain binding sites and an NXXY motif that, if phosphorylated, may be recognized by phosphotyrosine binding (PTB) domains. Comparison of the Lyp amino acid sequence with other known proteins shows 70% identity with the murine phosphatase PEP. The human Lyp gene was localized to chromosome 1p13 by fluorescence in situ hybridization analysis. We also identified an alternative spliced form of Lyp RNA, Lyp2. This isoform encodes a smaller 85-kD protein with an alternative C-terminus. The lyp phosphatases are predominantly expressed in lymphoid tissues and cells, with Lyp1 being highly expressed in thymocytes and both mature B and T cells. Increased Lyp1 expression can be induced by activation of resting peripheral T lymphocytes with phytohemagglutinin or anti-CD3. Lyp1 was found to be constitutively associated with the proto-oncogene c-Cbl in thymocytes and T cells. Overexpression of lyp1 reduces Cbl tyrosine phosphorylation, suggesting that it may be a substrate of the phosphatase. Thus, Lyp may play a role in regulating the function of Cbl and its associated protein kinases.
Alternative Splicing↗
The EH and SH3 domain Ese proteins regulate endocytosis by linking to dynamin and Eps15.
Clathrin-mediated endocytosis is a multistep process which requires interaction between a number of conserved proteins. We have cloned two mammalian genes which code for a number of endocytic adaptor proteins. Two of these proteins, termed Ese1 and Ese2, contain two N-terminal EH domains, a central coiled-coil domain and five C-terminal SH3 domains. Ese1 is constitutively associated with Eps15 proteins to form a complex with at least 14 protein-protein interaction surfaces. Yeast two-hybrid assays have revealed that Ese1 EH and SH3 domains bind epsin family proteins and dynamin, respectively. Overexpression of Ese1 is sufficient to block clathrin-mediated endocytosis in cultured cells, presumably through disruption of higher order protein complexes, which are assembled on the endogenous Ese1-Eps15 scaffold. The Ese1-Eps15 scaffold therefore links dynamin, epsin and other endocytic pathway components.
Adaptor Proteins, Signal Transducing↗
Survey in France of response to xenotransplantation.
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Adult↗
A new pressure attenuation index to evaluate retinal circulation. A link to protective factors in diabetic retinopathy.
BACKGROUND: Low ocular perfusion pressure (two thirds of mean arterial pressure minus intraocular pressure) and myopia have been associated with protection of the retina from clinical diabetic retinopathy. This prompts the question as to whether myopia's protective role could also be a pressure effect, given that pressure could be dissipated in the longer arteriole tree of the myopic eye. METHODS: We combined the Ohm, Poiseuille, and Murray laws to derive the following new formulation: the pressure attenuation along a vessel varies directly with its length and inversely with its diameter. A mean pressure attenuation index was calculated for 22 healthy control subjects, 25 patients with axial myopia, and 6 patients with retinitis pigmentosa using digitized fundus images. RESULTS: The myopic arteriolar tree would produce a 16% greater pressure attenuation than that of controls (P = .002), with a linear relationship between mean pressure attenuation index and axial length (r = 0.93). Mean pressure attenuation index of the group with retinitis pigmentosa is increased 67% above that of controls, which is calculated to contribute an additional 10 mm Hg of pressure dissipation along their retinal arteriolar system. CONCLUSIONS: Pressure attenuation in retinal arterioles is directly proportional to the length and inversely proportional to the diameter of the arteriole segment being measured. CLINICAL RELEVANCE: A pressure attenuation index may be important in light of the entities known or presumed to protect the retina from diabetic retinopathy. The results support the hypothesis that low-end arteriolar pressure is a common denominator for many protective conditions in diabetic retinopathy.
Blood Circulation↗
Education and peer discussion group interventions and adjustment to breast cancer.
BACKGROUND: We report a clinical trial comparing the effectiveness of education-based and peer discussion-based group interventions on adjustment to breast cancer. METHODS: Women with stage I, II, or III breast cancer (n = 312) were randomly assigned to 1 of 4 group conditions: control, education, peer discussion, or education plus peer discussion (combination). Seven groups (each comprising 8-12 women) were conducted in each of the 4 conditions (28 groups total). Adjustment was measured before the intervention, immediately after the intervention, and 6 months after the intervention. RESULTS: Consistently positive effects on adjustment were seen in the education groups both immediately following and 6 months after the intervention. There were no benefits of participation in peer discussion groups, and some indications of adverse effects on adjustment at both follow-up examinations. The effects could be explained by changes in self-esteem, body image, and intrusive thoughts about the illness. CONCLUSIONS: Education-based group interventions facilitated the initial adjustment of women diagnosed with early stage breast cancer. There was no evidence of benefits from peer discussion group interventions.
Adaptation, Psychological↗
Monoclonal anti-endothelial cell antibodies from a patient with Takayasu arteritis activate endothelial cells from large vessels.
OBJECTIVE: To create monoclonal anti-endothelial cell antibodies (mAECA) from a patient with Takayasu arteritis to evaluate their ability to activate human umbilical vein endothelial cells (HUVEC), and to characterize the mechanism of EC activation. METHODS: A panel of mAECA was generated from peripheral blood lymphocytes of a patient with Takayasu arteritis, using Epstein-Barr virus transformation. Activity against macrovascular EC (HUVEC) and microvascular EC (human bone marrow EC immortalized by SV40) antigens was detected by enzyme-linked immunosorbent assay. Inhibition studies were used to select the monoclonal antibodies (mAECA) which share the same EC epitope binding specificity as the total IgG-AECA from the Takayasu arteritis patient. The binding of the mAECA to human aortic EC was studied by immunohistochemistry. The secretion levels of interleukin-6 (IL-6) and von Willebrand factor (vWF) were determined, to serve as markers for EC activation. The activated EC were examined for the adherence of a monocytic cell line (U937), as well as for expression of vascular cell adhesion molecule 1, intercellular adhesion molecule 1, and E-selectin. In addition, nuclear extracts of the mAECA-treated EC were analyzed for the induction of translocation of nuclear factor kappaB (NF-kappaB), using a specific NF-kappaB oligoprobe in an electrophoretic mobility shift assay. RESULTS: Six mAECA were selected, the mixture of which produced 100% inhibition of binding of the original IgG (from the patient with Takayasu arteritis) to HUVEC. All mAECA possessed high activity against macrovascular EC, but none had significant antimicrovascular EC activity. The mAECA, but not normal human IgG, had anti-human aortic EC activity. Four of the 6 mAECA activated EC, manifested by increased IL-6 and vWF secretion. The 4 mAECA induced EC expression of adhesion molecules and increased adhesion of U937 monocytic cells to EC. In addition, these mAECA stimulated the nuclear translocation of the NF-kappaB transcription factor. CONCLUSION: Our findings suggest that AECA may directly stimulate EC in Takayasu arteritis through elevation of adhesion molecule expression associated with NF-kappaB activation and adhesion of monocytes, and may therefore play a pathogenic role in the development of the vasculopathy in Takayasu arteritis.
Adult↗
Risedronate therapy prevents corticosteroid-induced bone loss: a twelve-month, multicenter, randomized, double-blind, placebo-controlled, parallel-group study.
OBJECTIVE: Risedronate, a new pyridinyl bisphosphonate, is a potent antiresorptive bone agent. This study examines the safety and efficacy of daily, oral risedronate therapy for the prevention of corticosteroid-induced bone loss. METHODS: This multicenter, randomized, double-blind, placebo-controlled, parallel-group study was conducted in 224 men and women who were initiating long-term corticosteroid treatment. Patients received either risedronate (2.5 mg or 5 mg) or placebo daily for 12 months. Each patient also received 500 mg of elemental calcium daily. The primary outcome measure was the percentage of change in lumbar spine bone mineral density (BMD). Secondary measures included proximal femur BMD and incidence of vertebral fractures. RESULTS: After 12 months, the lumbar spine BMD (mean +/- SEM) did not change significantly compared with baseline in the 5-mg (0.6 +/- 0.5%) or the 2.5-mg (-0.1 +/- 0.7%) risedronate groups, while it decreased in the placebo group (-2.8 +/- 0.5%; P < 0.05). The mean differences in BMD between the 5-mg risedronate and the placebo groups were 3.8 +/- 0.8% at the lumbar spine (P < 0.001), 4.1 +/- 1.0% at the femoral neck (P < 0.001), and 4.6 +/- 0.8% at the femoral trochanter (P < 0.001). A trend toward a decrease in the incidence of vertebral fracture was observed in the 5-mg risedronate group compared with the placebo group (5.7% versus 17.3%; P = 0.072). Risedronate was well tolerated, and the incidence of upper gastrointestinal adverse events was comparable among the 3 groups. CONCLUSION: Risedronate therapy prevents bone loss in patients initiating long-term corticosteroid treatment.
Adolescent↗
Personality and tonic cardiovascular, neuroendocrine, and immune parameters.
Although there is now abundant evidence that certain personality features constitute risk factors for negative health outcomes, personality measures have received little attention to date in the behavioral immunology literature. The present study assessed the relationship between major dimensions of personality and tonic cardiovascular, neuroendocrine, and immunologic parameters in 276 healthy adults. Participants who scored low in agreeableness tended to have higher levels of systolic blood pressure, diastolic blood pressure, and epinephrine. Low levels of extraversion were associated with higher blood pressure, epinephrine, norepinephrine, and natural killer cell cytotoxicity. Neuroticism was generally unrelated to physiologic outcomes. Personality was not associated with leukocyte subset counts. The magnitude of relationships between personality and physiology was modest, with personality measures accounting for 1 to 7% of the variance in selected physiological parameters. Health practices did not mediate associations between personality and physiologic outcomes. However, a substantial proportion of the relationship between extraversion and natural killer cell cytotoxicity was accounted for by their common association with epinephrine and to a lesser extent norepinephrine. These findings are consistent with the notion that personality contributes to basal physiology and provide a foundation for further research on the relationship between personality and natural killer cell cytotoxicity.
Adolescent↗
Negative emotions and acute physiological responses to stress.
One pathway through which stressors are thought to influence physiology is through their effects on emotion. We used meta-analytic statistical techniques with data from nine studies to test the effects of acute laboratory stressors (speech, star mirror-image tracing, handgrip) on emotional (undifferentiated negative emotion, anger, anxiety) and cardiovascular (CV) response. In all of the studies, participants responded to stressors with both increased CV response and increased negative emotion. Increases in negative emotion were associated with increases in CV response across tasks, however, these associations were small. The range of variance accounted for was between 2% and 12%. Thus, the contribution of negative emotion, as assessed in these studies, to physiological responses to acute laboratory stressors was limited. Although these results raise questions about the role of emotion in mediating stress-elicited physiological responses, the nature of the acute laboratory stress paradigm may contribute to the lack of a strong association.
Acute Disease↗
Studies with rasagiline, a MAO-B inhibitor, in experimental focal ischemia in the rat.
Rasagiline, as the mesylate salt (TVP-1012), is a selective, potent, non-reversible MAO-B inhibitor of the propargylamine type. Current cellular and whole animal studies suggested a potential for neuroprotection by rasagiline. Rasagiline in repeat ip doses of 1-3mg/kg within 16h, or by sustained iv infusion to maintain a 3-h steady-state at corresponding levels, improved the outcome of permanent middle cerebral artery occlusion (MCAO) in the rat. In five independent studies using different protocols, rasagiline improved neurological severity score (NSS) with respect to saline from a high of 8.96 +/- 2.18 (n = 94) at 24h, and 7.64 +/- 2.52 (n +/- 49) at 48h, to a low of 7.13 +/- 2.32 (n = 88) at 24h, and 4.99 +/- 2.31 (n = 68) at 48h. Under the same conditions, there was a decrease in the volume of necrotic brain region determined at 48h by triphenyl tetrazolium chloride (TTC), from a high of 240 +/- 66 (n = 54) to a low of 176 +/- 77 mm(3) (n = 55); and by MRI scan at 48h, from a high of 297 +/- 62 (n = 25), to a low of 209 +/- 63 mm(3) (n = 28). Improvement in NSS was more obvious at 48h post MCAO, at the higher dose, when timing of drug administration was within the interval -30 min to 3 h from MCAO. A 3-h iv infusion of rasagiline caused a maximal reduction in infarct volume of about 49% of control. The (S)enantiomer of rasagiline TVP-1022, not a MAO inhibitor, was less effective, but still significantly different from saline, NSS at 48h 5.6 +/- 2.5 (n = 24) vs. 7.5 +/- 2.5 (n = 24), infarct volume 200 +/- 64 (n = 24) vs. 240 +/- 55 mm(3) (n = 24). Selegiline (n = 19) at corresponding ip doses was not different from saline. Dizocilpine decreased infarct volume from 277 +/- 65 (n = 20) to 203 +/- 52mm(3) (n = 21) but could not improve NSS at 24 or 48h. In this model, rasagiline could have exerted a neuroprotective effect independent of MAO inhibition.
Animals↗
Clozapine lacks previous clinical efficacy when restarted after a period of discontinuation: a case series.
No data are available in the literature about clozapine clinical efficacy when the drug is administered to schizophrenic patients who relapsed after discontinuation of long-term clozapine treatment and who had previously been responsive to the drug. In this study, three chronic schizophrenic patients are presented, who, in spite of a good clinical efficacy, decided to stop long-term clozapine treatment. Soon after their relapse they were again treated with clozapine: follow-up of these patients showed that clozapine partially lost its clinical efficacy since all three patients got worse compared with their initial clinical response.
Adult↗
The effect of region of interest variations on morphologic operations data and gray-level values extracted from digitized dental radiographs.
OBJECTIVE: To determine the correlations among morphologic operations (MO) values and the correlations among gray-level values for regions of interest (ROIs) placed at various locations on digital images of alveolar bone for 45 patients. STUDY DESIGN: As part of a larger study, up to 7 vertical bite-wing radiographs were taken and digitized for each of 45 patients. Sets of 2 rectangular ROIs were placed on the digitized images of interdental alveolar bone at 4 locations for each patient. The ROIs (1 crestal and 1 apical) were placed between second premolars and first molars in all 4 dental quadrants. Gray-level values were measured, and MO analysis was performed on each ROI. Descriptive statistics were calculated and correlations determined. RESULTS: Paired correlations (such as apical vs crestal, left vs right, maxillary apical vs mandibular apical) of MO values were weak (r = 0.01-0.21), but corresponding correlations for gray-level values were relatively strong (r = 0. 60-0.92). CONCLUSION: MO values varied with ROI location considerably more than did gray-level values. Additionally, ROI size and shape apparently affected MO data. Accurate placement and documentation of ROIs appear to be critical considerations in analyses that use MOs.
Alveolar Bone Loss↗