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Biomedical subjects

N Rao

Publications and source records attributed to N Rao.

At least 19 recordsLinked to original sources
PubMed2001

The non-receptor tyrosine kinase Syk is a target of Cbl-mediated ubiquitylation upon B-cell receptor stimulation.

The negative regulator Cbl functions as a ubiquitin ligase towards activated receptor tyrosine kinases and facilitates their transport to lysosomes. Whether Cbl ubiquitin ligase activity mediates its negative regulatory effects on cytoplasmic tyrosine kinases of the Syk/ZAP-70 family has not been addressed, nor is it known whether these kinases are regulated via ubiquitylation during lymphocyte B-cell receptor engagement. Here we show that B-cell receptor stimulation in Ramos cells induces the ubiquitylation of Syk tyrosine kinase which is inhibited by a dominant-negative mutant of Cbl. Intact tyrosine kinase-binding and RING finger domains of Cbl were found to be essential for Syk ubiquitylation in 293T cells and for in vitro Syk ubiquitylation. These same domains were also essential for Cbl-mediated negative regulation of Syk as measured using an NFAT-luciferase reporter in a lymphoid cell. Association with Cbl did not alter the kinase activity of Syk. Altogether, our results support an essential role for Cbl ubiquitin ligase activity in the negative regulation of Syk, and establish that ubiquitylation provides a mechanism of Cbl-mediated negative regulation of cytoplasmic targets.

Cell Line↗
PubMed2001

Orbital presentations of giant cell arteritis.

BACKGROUND: giant cell arteritis (GCA) is a systemic vasculitis that may affect the optic nerve and cause blindness (e.g. ischemic optic neuropathy). Orbital inflammatory disease, however, is an uncommon presentation of GCA. PURPOSE: to alert clinicians to the orbital presentations of GCA. PATIENTS AND METHODS: a retrospective case series from tertiary care academic ophthalmic referral centers of four patients with orbital manifestations of giant cell arteritis. RESULTS: presentation of cases and review of the literature. In three cases, a temporal artery biopsy was diagnostic of GCA, but in one case, an orbital biopsy was needed to confirm the diagnosis. CONCLUSION: GCA can have orbital manifestations and clinicians should be aware of this unusual presentation of GCA in cases of presumed orbital inflammatory pseudotumor in the elderly.

Aged↗
PubMed2001

Characterization of the Co(2+) and Ni(2+) binding amino-acid residues of the N-terminus of human albumin. An insight into the mechanism of a new assay for myocardial ischemia.

Patients suffering from myocardial ischemia reportedly exhibit reduced in vitro binding of exogenous Co(2+) to the N-terminal of human serum albumin (HSA). The purpose of our investigation was to simulate changes in the N-terminus of HSA that may account for these ischemia-induced modifications to the cobalt binding site. HPLC, LC-MS and (1)H NMR analyses have shown that the N-terminal region of HSA Asp-Ala-His-Lys binds the transition metals Co(2+) and Ni(2+). Synthetic peptides with the first 2-12 amino acids of the HSA sequence demonstrated that the first three amino acids, Asp-Ala-His, are essential for strong binding of cobalt. Modification of the N-terminus peptide of HSA by way of N-acetylation or the deletion of one or more amino acid resulted in no binding of cobalt. Because the degradation of the susceptible, specific transition metal binding site of HSA may account for the decreased cobalt binding observed during ischemic events, an assay that detects this reduced binding could be useful in the diagnosis of ischemia.

Alanine↗
PubMed2001

Preliminary results of a randomized controlled trial of prophylactic shock wave lithotripsy for small asymptomatic renal calyceal stones.

OBJECTIVE: To report a prospective, randomized study to determine whether prophylactic extracorporeal shockwave lithotripsy (ESWL) is justified as a treatment for small, asymptomatic calyceal stones. PATIENTS AND METHODS: The study included 228 patients with small (< 15 mm total diameter) asymptomatic calyceal stones; 113 patients were randomized to undergo ESWL and 115 to the control group who were kept under observation. Outcome measurements included the stone-free rate, requirement for additional treatment, symptoms, quality of life and renal function. RESULTS: In all, 200 patients had at least one annual follow-up; all outcome measurements reported were those at the most recent follow-up (mean 2.2 years, range 1-5). In the ESWL group 28 patients (28%) were stone-free, compared with 16 (17%) in the observation group (odds ratio 1.95, 95% confidence interval, CI, 0.97-3.89, P = 0.06). Additional treatment in the form of analgesics, antibiotics, ESWL, stent insertion and ureteroscopy, was required in 21 (21%) patients in the observation group and 15 (15%) in the ESWL group (odds ratio 0.66, 95% CI 0.32-1.37, P = 0.27). Ten patients in the observation group required invasive procedures, vs none in the ESWL group. There was no evidence of differences in the symptoms, quality of life or renal function tests between the arms of the trial at the final follow-up. CONCLUSIONS: Prophylactic ESWL for small asymptomatic renal calyceal stones does not appear to offer any advantage to patients in terms of stone-free rate, quality of life, renal function, symptoms or hospital admissions. However, a policy of observation is associated with a greater risk of requiring more invasive procedures. A longer follow-up is required to assess the validity of these preliminary findings.

Adult↗
PubMed2001

Bilateral, simultaneous, spontaneous rupture of quadriceps tendons without trauma in an obese patient: a case report.

This is a single case report of bilateral, simultaneous, spontaneous rupture of the quadriceps tendon caused by obesity without trauma. The patient was a 52-year-old, 350-pound, morbidly obese man with a sedentary life style whose quadriceps tendons ruptured while he was descending a staircase. He presented with a large deficit superior to the patella and an inability to straighten his knees. After surgery, his knees were immobilized in extension for 6 weeks, followed by gradual weight bearing and gait training with braces. He was weaned off the braces as he increased the range of motion and strength in his knees. The rehabilitation process was protracted, and he returned to full-time work 6 months postinjury. Physiatrists should be familiar with the diagnosis, treatment, and rehabilitation of this rare condition.

Humans↗
PubMed2001

Electromyography and computed tomography scan-guided fine needle aspiration biopsy of discrete extraocular muscle metastases.

Discrete or isolated metastasis to the extraocular muscles without an accompanying intraconal or extraconal mass is rare. Although it is estimated that 5% of orbital metastasis involves extraocular muscles only, to our knowledge there are no reports of discrete extraocular muscle involvement from renal cell carcinoma. With discrete extraocular muscle involvement, accurate localization within the infiltrated region of the muscle is of paramount importance in achieving a safe and positive biopsy. We describe a case with discrete extraocular muscle metastasis from a renal cell carcinoma, where a novel technique of FNAB (fine needle aspiration biopsy) of the medial rectus was undertaken, with EMG (electromyography) control and CT (computerized tomography) scan guidance.

Aged↗
PubMed2001

Invasive aspergillosis outbreak on a hematology-oncology ward.

An outbreak of invasive aspergillosis occurred in a community hospital in temporal association with construction activity. Epidemiological investigation showed that patients who are at highest risk comprise a small group and are readily identifiable. Clinicians should strive to protect these patients, following guidelines published by the Centers for Disease Control and Prevention.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2001

MADD victim impact panels and stages-of-change in drunk-driving prevention.

OBJECTIVE: To assess the additional effects of Mothers Against Drunk Driving (MADD) Victim Impact Panels (VIPs) over the effects of a DWI (driving while intoxicated) school, on (1) moving individuals through the stages-of-change toward not drinking while driving and (2) drunk-driving recidivism. METHOD: A randomized experiment with 813 (75% male) DWI offenders in New Mexico measured progress through the stages-of-change at pretest, posttest, 1-year follow-up and 2-year follow-up. In addition, drunk-driving recidivism over 2 years was measured from state driving records. Individuals were randomly assigned to a DWI school or a DWI school plus a MADD VIP. RESULTS: No significant difference in movement through the stages-of-change, or in recidivism, occurred between respondents in the DWI-school-only treatment, and those in the DWI school plus VIP treatment. CONCLUSIONS: There was no additional effect of the MADD VIP, a relatively emotional intervention, over that of the DWI school, a relatively informational approach, on DWI behavior (whether measured by stages-of-change or by DWI rearrest data) over the 2-year period following the two interventions.

Adult↗
PubMed2000

The linker phosphorylation site Tyr292 mediates the negative regulatory effect of Cbl on ZAP-70 in T cells.

The protooncogene product Cbl has emerged as a negative regulator of tyrosine kinases. We have shown previously that Cbl binds to ZAP-70 through its N-terminal tyrosine kinase binding (TKB) domain. In this study, we demonstrate that overexpression of Cbl in Jurkat T cells decreases the TCR-induced phosphorylation of ZAP-70 and other cellular phosphoproteins. Coexpression of Cbl with ZAP-70 in COS cells reproduced the Cbl-induced reduction in the level of phosphorylated ZAP-70. The effect of Cbl was eliminated by the TKB-inactivating G306E mutation in Cbl as well as by a phenylalanine mutation of Tyr292 within the TKB domain binding site on ZAP-70. Notably, the oncogenic Cbl-70Z/3 mutant associated with ZAP-70, but did not reduce the levels of phosphorylated ZAP-70. Overexpression of Cbl, but not Cbl-G306E, in Jurkat T cells led to a decrease in the TCR-induced NF-AT luciferase reporter activity. Overexpression of the TKB domain itself, but not its G306E mutant, functioned in a dominant-negative manner and led to an increase in NF-AT reporter activity. Cbl-70Z/3-overexpressing cells exhibited an increase in both basal and TCR-induced NF-AT luciferase reporter activity, and this trend was reversed by the G306E mutation. Finally, by reconstituting a ZAP-70-deficient Jurkat T cell line, p116, we demonstrate that wild-type ZAP-70 is susceptible to the negative regulatory effect of Cbl, whereas the ZAP-70-Y292F mutant is resistant. Together, our results establish that the linker phosphorylation site Tyr292 mediates the negative regulatory effect of Cbl on ZAP-70 in T cells.

Animals↗
PubMed2000

The RING finger domain of Cbl is essential for negative regulation of the Syk tyrosine kinase.

The proto-oncogene product Cbl has emerged as a negative regulator of a number of protein-tyrosine kinases, including the ZAP-70/Syk tyrosine kinases that are critical for signaling in hematopoietic cells. The evolutionarily conserved N-terminal tyrosine kinase-binding domain is required for Cbl to associate with ZAP-70/Syk and for their subsequent negative regulation. However, the role of the remaining C-terminal regions of Cbl remains unclear. Here, we used a COS-7 cell reconstitution system to address this question. Analysis of a series of C-terminally truncated Cbl mutants revealed that the N-terminal half of the protein, including the TKB and RING finger domains, was sufficient to mediate negative regulation of Syk. Further truncations, which delete the RING finger domain, abrogated the negative regulatory effects of Cbl on Syk. Point mutations of conserved cysteine residues or a histidine in the RING finger domain, which are required for zinc binding, abrogated the ability of Cbl to negatively regulate Syk in COS-7 cells and Ramos B lymphocytic cells. In addition, Syk-dependent transactivation of a serum response element-luciferase reporter in transfected 293T cells was reduced by wild type Cbl; mutations of the RING finger domain or its deletion abrogated this effect. These results establish the RING finger domain as an essential element in Cbl-mediated negative regulation of a tyrosine kinase and reveal that the evolutionarily conserved N-terminal half of the protein is sufficient for this function.

Amino Acid Sequence↗
PubMed2000

Motivational Beliefs, Study Strategies, and Mathematics Attainment in High- and Low-Achieving Chinese Secondary School Students.

In order to examine the relationship between cognitive and motivational variables and their relationship to mathematics attainment, Hong Kong-Chinese students enrolled in schools for high-, average-, and low-achievers completed questionnaires in Year 10 and in Year 11. Low-achievers perceived academic learning as being less useful over time and reported spending less time studying in Year 10 than in Year 11 but high- and low-achievers did not differ on their use of self-regulated learning strategies. Performance on the public examination in mathematics was predicted by prior achievement and Self-Concept of Mathematics Ability. Results underscore the importance of considering cultural beliefs systems and educational systems in models of academic motivation. Copyright 2000 Academic Press.

Journal Article↗
PubMed2000

A biodialysis system for liver support tested in a porcine hepatic failure model.

BACKGROUND: A practical liver support system for patients in fulminant hepatic failure (FHF) remains a needed therapeutic modality. A new method of bioartificial liver support, the liver biodialysis system (LBDS), is described. METHODS: Porcine hepatocytes, removed from direct contact with the treated subject's circulation, are in culture in a bioreactor which is combined in a dialysis circuit for patient treatment. The LBDS was tested in a porcine ischaemic hepatic failure model. RESULTS: The viable hepatocyte content of the bioreactor was 2.49 +/- 0.72 x 10(10). Cells remained viable in culture throughout the experiments (30 +/- 3 h) without evidence of immunological damage. A decrease in the degree of accumulation in the blood of ammonia (P < 0.02) and of 14 amino acids (P < 0.001) was achieved by the LBDS. Cerebral perfusion pressure was maintained at significantly higher levels in LBDS-treated animals (P < 0.05). CONCLUSIONS: In the LBDS, hepatocytes in large numbers and satisfactory culture conditions in a bioreactor have sustained viability and function. When combined in a dialysis circuit for the treatment of FHF pigs, immune reactions between the blood and hepatocytes were prevented and beneficial metabolic effects were observed.

Amino Acids↗
PubMed2000

The relative rapidity of recanalization induced by recombinant tissue-type plasminogen activator (r-tPA) and TNK-tPA, assessed with enzymatic methods.

BACKGROUND: Comparison of different plasminogen activators is difficult because conventional endpoints such as mortality are relatively insensitive to potential differences in efficacy with respect to rapidity of recanalization of infarct-related arteries. METHODS: This study was performed to determine whether valid comparisons could be made by means of biochemical endpoints that have been demonstrated previously to permit estimation of the time of opening of an infarct-related artery in experimental animals and in patients. The method is based on time-dependent interconversion of isoforms of creatine kinase mediated by carboxypeptidase N, an enzyme present in excess in circulating blood. A small subset of 39 patients studied in the ASsessment of the Safety and Efficacy of a New Thrombolytic agent (ASSENT-2) trial were evaluated to determine the feasibility of using the creatine kinase isoform method for comparison of two tissue-type plasminogen activators (tPA), recombinant tPA (r-tPA) and TNK-tPA. RESULTS: Early recanalization (within 40 min of the onset of treatment with the plasminogen activator) occurred in 56% of patients treated with r-tPA and 76% of those treated with TNK-tPA. CONCLUSIONS: Differences in the efficacy of plasminogen activators with respect to rapidity of recanalization appear to be readily detectable by means of assaying creatine kinase isoforms in serially acquired blood samples under conditions that permit widespread application of the approach developed.

Biomarkers↗
PubMed1999

Molecular characterization of a third member of the guanylyl cyclase-activating protein subfamily.

The mammalian retina contains at least two guanylyl cyclases (GC1 and GC2) and two guanylyl cyclase-activating proteins (GCAP1 and GCAP2). Here we present evidence of the presence of a new photoreceptor-specific GCAP, termed GCAP3, which is closely related to GCAP1. The sequence similarity of GCAP3 with GCAP1 and GCAP2 is 57 and 49%, respectively. Recombinant GCAP3 and GCAP2 stimulate GC1 and GC2 in low [Ca2+]free and inhibit GCs when [Ca2+]free is elevated, unlike GCAP1, which only stimulates GC1. GCAP3 is encoded by a distinct gene present in other mammalian species but could not be detected by genomic Southern blotting in rodents, amphibians, and lower vertebrates. The intron/exon arrangement of the GCAP3 gene is identical to that of the other GCAP genes. While the GCAP1 and GCAP2 genes are arranged in a tail-to-tail array on chromosome 6p in human, the GCAP3 gene is located on 3q13.1, suggesting an ancestral gene duplication/translocation event. The identification of multiple Ca2+-binding proteins that interact with GC is suggestive of complex regulatory mechanisms for photoreceptor GC.

Amino Acid Sequence↗
PubMed1999

Positional isomers of acetaminophen differentially induce proliferation of cultured breast cancer cells.

This study demonstrates that acetaminophen (p-acetamidophenol) stimulates proliferation of estrogen-responsive cultured breast cancer cells and assesses if the proliferative activity of p-acetamidophenol is influenced by the -OH moiety position on the benzene ring. The effects of p-, m-, and o-acetamidophenol on cell number and on percentage cells in S phase of the cell cycle were determined for two estrogen receptor positive, human breast cancer cell lines, T47D and MCF7. Therapeutic concentrations of p-acetamidophenol (0.1 mM) significantly increased breast cancer cell proliferation. The relative order of potency of isomers in stimulating proliferation in both cell types was p- > m- > o-acetamidophenol, indicating the -OH position on the benzene ring influences the proliferation output in cultured breast cancer cells.

Acetaminophen↗
PubMed1999

The systemic safety of fexofenadine HCl.

Fexofenadine is a highly specific, H1-receptor antagonist with a safety profile similar to placebo. In placebo-controlled trials of seasonal allergic rhinitis (SAR) and chronic idiopathic urticaria (CIU), the type and incidence of adverse events were comparable in fexofenadine and placebo recipients. Fexofenadine does not impair performance in tests of driving or psychomotor performance and has been shown to improve quality of life in patients with SAR. Fexofenadine has a high margin of safety and is also well tolerated in subjects with renal or hepatic impairment, in children and the elderly. No clinically significant drug interactions have been identified. Fexofenadine is not associated with cardiotoxicity. Unlike some other antihistamines, such as loratidine or cetirizine [1, 2], fexofenadine is truly non-sedating, showing no dose-related increase in sedation, even at high doses [3, 4]. Fexofenadine is formulated and marketed as the hydrochloride salt. The recommended dose of fexofenadine HC1 is 120 mg daily for SAR (either as 120 mg once daily or 60 mg twice daily) or 180 mg once daily for CIU.

Aged↗