Spontaneous resolution of a pituitary mass: probable lymphocytic hypophysitis.
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Adult↗
Biomedical subjects
N Shah
Publications and source records attributed to N Shah.
Insulin-induced egr-1 expression in Chinese hamster ovary cells is insulin receptor and insulin receptor substrate-1 phosphorylation-independent. Evidence of an alternative signal transduction pathway.
Insulin's effects primarily are initiated by insulin binding to its plasma membrane receptor and the sequential tyrosine phosphorylation of the insulin receptor and intracellular substrates, such as insulin receptor substrate-1 (IRS-1). However, studies suggest some insulin effects, including those at the nucleus, may not be regulated by this pathway. The present study compared the levels of insulin binding, insulin receptor and IRS-1 tyrosine phosphorylation, and phosphatidylinositol 3'-kinase activity to immediate early gene c-fos and egr-1 mRNA expression in Chinese hamster ovary (CHO) cells expressing only neomycin-resistant plasmid (CHONEO), overexpressing wild type human insulin receptor (CHOHIRc) or ATP binding site-mutated insulin receptors (CHOA1018K). Insulin binding in CHONEO cells was markedly lower than that in other cell types. 10 nM insulin significantly increased tyrosine phosphorylation of insulin receptor and IRS-1 in CHOHIRc cells. Phosphorylation of insulin receptor and IRS-1 in CHONEO and CHOA1018K cells was not detected in the presence or absence of insulin. Similarly, insulin increased phosphatidylinositol 3-kinase activity only in CHOHIRc cells. As determined by Northern blot, nuclear run-on analysis, and in situ hybridization, insulin induced c-fos mRNA expression, through transcription, in CHOHIRc cells but not in CHONEO and CHOA1018K cells, consistent with previous reports. In contrast, all three cell types showed a similar insulin dose-dependent increase of egr-1 mRNA expression through transcription. These data indicated that insulin-induced egr-1 mRNA expression did not correlate with the levels of insulin binding to insulin receptor or phosphorylation of insulin receptor and IRS-1. These results suggest that different mechanisms are involved in induction of c-fos and egr-1 mRNA expression by insulin, the former by the more classic insulin receptor tyrosine kinase pathway and the latter by a yet to be determined alternative signal transduction pathway.
Adenosine Triphosphate↗
Regulation of constitutive nitric oxide synthase activity by the human heart.
We and others have provided indirect evidence for the presence of a constitutive nitric oxide synthase (cNOS) in the mammalian heart. We now provide more direct evidence for the regulation of a myocardial cNOS in the hearts of patients undergoing elective cardiopulmonary bypass (CPB). cNOS enzyme activity was demonstrable in both cytosolic (8.3 +/- 0.02 pmol/min/mg) and membrane (11.1 +/- 0.4 pmol/min/mg) preparations derived from human atrial pectinate muscles obtained at the time of CPB (n = 6). Plasma nitrite (NO2-) + plasma nitrate (NO3-) levels from the beating hearts of patients before bypass were reduced from 146 +/- 33 to 5.1 +/- 50 pmol/min/g after cardiac arrest during CPB (n = 23; p < 0.002 by Student's t test). Thus, the human myocardium constitutively produces nitric oxide that is regulated by the contractile state of the heart.
Adult↗
Introduction of an activated N-ras oncogene alters the growth characteristics of the interleukin 6-dependent myeloma cell line ANBL6.
Multiple myeloma (MM) is a late-stage B-cell cancer with an unknown etiology. Activating mutations of the N-ras and K-ras oncogenes occur with a high frequency in myeloma and, therefore, may play a role in the pathogenesis of the disease. To study the role of N-ras-activating mutations in the regulation of myeloma tumor growth, we introduced a constitutively active N-ras cDNA containing a glutamine to arginine (CAA-CGA) amino acid substitution at codon 61 into the interleukin 6 (IL-6)-dependent myeloma cell line ANBL6. Expression of the mutant N-ras cDNA resulted in significant IL-6-independent growth, as well as augmentation of growth at suboptimal concentrations of IL-6. The IL-6-independent growth pattern was not the result of activation of autocrine IL-6 production in the mutant N-ras-expressing population because neutralizing antibodies to the IL-6 receptor and to IL-6 had no effect on the rate of DNA synthesis in the absence of IL-6. Furthermore, mutant N-ras expression decreased the percentage of cells undergoing apoptosis in the absence of IL-6. These data suggest that activating mutations of the ras oncogenes may result in growth factor independence accompanied by a suppression of apoptosis in MM. Therefore, the use of therapies designed to block IL-6 action in MM may have less of an impact on tumors bearing activated ras mutations.
Apoptosis↗
Demonstration of specific insulin binding to cytosolic proteins in H35 hepatoma cells, rat liver and skeletal muscle.
We previously demonstrated that internalized insulin enters the cytoplasm before accumulating in nuclei of H35 rat hepatoma cells. This finding raises the possibility that insulin may interact with cytosolic proteins in addition to insulin-degrading enzyme (IDE). In the present study, cytosol from H35 hepatoma cells, rat liver or muscle was incubated with A14- or B26-125I-insulin at 4 degrees C for 5-120 min in the absence or presence of 25 micrograms/ml unlabelled insulin. 125I-insulin was cross-linked to cytosolic proteins by disuccinimidyl suberate and analysed by reducing or non-reducing SDS/PAGE and autoradiography. Our results demonstrate the presence of both tissue-specific and common cytosolic proteins which specifically bind insulin. In muscle cytosol, only two proteins of 27 and 110 kDa were specifically labelled with B26-125I-insulin. Seven major bands, of 27, 45, 55, 60, 76, 82 and 110 kDa, were labelled in rat liver cytosol. Detection of cytosolic insulin-binding proteins in H35-cell cytosol was dependent on cell-culture conditions. Labelling in cytosol from serum-deprived cells was decreased or absent compared with cytosol prepared from serum-fed or serum-deprived cells treated with 100 ng/ml insulin for 1 h before preparation of the cytosol, in which six bands, of 32, 41, 45, 55, 82 and 110 kDa, were specifically labelled with B26-125I-insulin. This result suggests that the concentration or binding activity of some cytosolic insulin-binding proteins is rapidly regulated. Labelling of both rat liver and H35 cytosolic insulin-binding proteins was time-dependent, and decreased or disappeared at 120 min in parallel with the degradation of labelled insulin. Fewer bands were specifically labelled with A14-125I-insulin than with B26-125I-insulin. The number of labelled bands observed under reducing and non-reducing conditions was not different in any of the cytosols. The 110 kDa band in all cytosols was identified as IDE by Western-blot analysis; the other proteins did not react with anti-IDE antibody and remain unidentified. 1,10-Phenanthroline (2 mM) increased IDE labelling, but decreased the labelling of 82 and 27 kDa bands. The marked difference in the number of cytosolic insulin-binding proteins in muscle and either H35 cells or liver suggests both that the labelling is specific and that these proteins serve a function and may be involved in some heretofore unknown mechanism of the signalling pathway by which insulin regulates cell growth or differentiation.
Animals↗
The cellular function of MASH1 in autonomic neurogenesis.
Using primary cultures and immortalized multipotential stem cell lines derived from wild-type and Mash1 mutant neural crest cells, we have analyzed the cellular function of MASH1 in autonomic neurogenesis. We present evidence for the existence of a precursor expressing MASH1 and neuronal markers such as neurofilament, neuron-specific tubulin, and tetanus toxin receptor. This cell has a nonneuronal morphology. Differentiation of this precursor to neurons that express markers such as SCG10, peripherin, and neuron-specific enolase is dependent upon MASH1 function. These data imply that the differentiation of autonomic neurons from uncommitted neural crest cells occurs in several sequential steps. Moreover, they suggest that MASH1 does not commit multipotent cells to a neural fate, like its Drosophila achaete-scute counterparts, but rather promotes the differentiation of a committed neuronal precursor.
Animals↗
Biofeedback therapy in poststroke rehabilitation: a meta-analysis of the randomized controlled trials.
OBJECTIVE: To assess the efficacy of biofeedback therapy in poststroke rehabilitation. DESIGN: A meta-analysis of the reported randomized control trials of biofeedback therapy in poststroke rehabilitation was performed. Data were analyzed using the effect size method and pooled using the Der Simonian-Laird Random Effects Model. Study quality was assessed according to the method of Chalmers. SETTING: All included studies were conducted in academically based rehabilitation settings. PATIENTS: Patients were in the rehabilitative phase of their illness. The timing of the intervention from the acute event did vary greatly between and within studies. INTERVENTION: Biofeedback therapy was applied to a paretic limb of patients in the study group. Both treatment and control groups received standard physical therapy. MAIN OUTCOME MEASURE: Change in range of motion of a joint of a paretic limb as a result of treatment was examined. This measure was chosen after the eligible studies were evaluated for combinable end points. RESULTS: A total of eight studies were included in the analysis. The mean effect size for change in lower extremity range of motion as a result of biofeedback therapy was 1.50 (95% confidence interval [CI]: -0.59, 3.59). For the upper extremity the effect size was 2.30 (95% CI: -1.06, 5.66). Both results were not significant at the p < .05 level. Statistical tests showed significant heterogeneity among studies, validating the use of the Random Effects Model. CONCLUSION: Results of pooling available randomized control trials do not support the efficacy of biofeedback in restoring the range of motion of hemiparetic joints. Nevertheless, because the calculated mean effect sizes were large, with associated wide confidence intervals, the possibility of a type II error masking an important clinical benefit needs to be considered in evaluating this result.
Arm↗
Primitive neuroectodermal tumor of maxilla in an adult.
Primitive neuroectodermal tumor is primarily a central nervous system tumor. These tumors are generally manifest in infancy or early childhood. The following article reports a rare case of primitive neuroectodermal tumor in posterior maxilla in an adult. Treatment for primitive neuroectodermal tumor in extracranial sites in adults is not clearly defined in the literature. This case was treated by combined chemotherapy followed by radiotherapy, which failed to cause regression of the lesion.
Adult↗
Increased serum nitrite and nitrate concentrations in children with the sepsis syndrome.
OBJECTIVES: To measure total serum nitrite and nitrate concentrations in children with the sepsis syndrome as an indicator of endogenous nitric oxide production. To determine if there is an association between total serum nitrite and nitrate concentrations and vascular responsiveness to norepinephrine. DESIGN: A prospective, clinical study. SETTING: Tertiary, multidisciplinary, pediatric intensive care unit. PATIENTS: Thirty-one children with the sepsis syndrome, 18 of whom were also hypotensive. Sixteen critically ill children without signs of the sepsis syndrome served as controls. INTERVENTIONS: Blood samples were obtained from indwelling catheters. The norepinephrine dose to reach the age appropriate, 50th percentile mean arterial blood pressure was determined in patients receiving norepinephrine. MEASUREMENTS AND MAIN RESULTS: Total serum nitrite and nitrate concentrations were measured on the first three days after the recognition of the sepsis syndrome. Patients with the sepsis syndrome had increased mean total serum nitrite and nitrate concentrations (day 1, 118 +/- 93 microM; day 2, 112 +/- 94 microM; day 3, 112 +/- 93 microM) vs. controls (43 +/- 24 microM, p < .05) on all 3 days. When sepsis syndrome patients were separated into nonhypotensive and hypotensive groups, only the patients with hypotension had increased concentrations vs. controls on all three days (p < .05). Sepsis syndrome patients with hypotension also had higher total serum nitrite and nitrate concentrations (145 +/- 97 microM) than sepsis syndrome patients without hypotension (82 +/- 76 microM, p < .05) on day 1. In five patients receiving norepinephrine infusions, increased total serum nitrite and nitrate concentrations were associated with higher norepinephrine requirements to maintain an age-appropriate, 50th percentile mean arterial blood pressure on each of the three study days (day 1, rs = 0.821, p < .05; day 2, rs = 0.900, p < .05; day 3, rs = 0.872, p < .05). CONCLUSIONS: Children with the sepsis syndrome, particularly those patients with hypotension, have increased total serum nitrite and nitrate concentrations that likely reflect increased endogenous production of nitric oxide. Vascular hyporesponsiveness to norepinephrine during the sepsis syndrome may be, in part, a nitric oxide-mediated process.
Adolescent↗
Colonoscope length and procedure efficiency.
We reviewed 195 colonoscopies to determine whether procedure efficiency differed with the use of an intermediate-length (135 cm) colonoscope compared with a long (165 cm) colonoscope. The cecum was intubated with the 135-cm scope in 92.6% of procedures and with the 165-cm colonoscope in 96.8% of procedures (chi 2 method, p = 0.26). The mean procedure duration was 36.7 min for 107 complete procedures performed with the 135-cm colonoscope and 48.4 min for 55 examinations using the 165-cm colonoscope (t test, p < 0.001). Colonoscopy with the 135-cm instrument required mean meperidine and midazolam doses of 59.9 mg and 1.8 mg, respectively, compared with doses of 69.1 mg and 2.0 mg, respectively, with the 165-cm colonoscope. The differences were not significant. Although the cecal intubation rate is slightly less for the 135-cm colonoscope, insertion takes significantly less time and is probably more comfortable for the patient than with the 165-cm colonoscope.
Adult↗
Meta-analysis of randomized controlled trials of cranial electrostimulation. Efficacy in treating selected psychological and physiological conditions.
To clarify the diverse published results of cranial electrostimulation (CES) efficacy, we conducted an extensive literature review that identified 18 of the most carefully conducted randomized controlled trials of CES versus sham treatment. For the 14 trials that had sufficient data, we used the techniques of meta-analysis to pool the published results of treating each of four conditions: anxiety (eight trials), brain dysfunction (two trials), headache (two trials), and insomnia (two trials). Because studies utilized different outcome measures, we used an effect size method to normalize measures which we then pooled across studies within each condition. The meta-analysis of anxiety showed CES to be significantly more effective than sham treatment (p < .05). Pooling did not affect results that were individually positive (headache and pain under anesthesia) or negative (brain dysfunction and insomnia). Most studies failed to report all data necessary for meta-analysis. Moreover, in all but two trials, the therapist was not blinded and knew which patients were receiving CES or sham treatment. We strongly recommend that future trials of CES report complete data and incorporate therapist blinding to avoid possible bias.
Anxiety Disorders↗
Binding, uptake, and intracellular trafficking of phosphorothioate-modified oligodeoxynucleotides.
An enhanced appreciation of uptake mechanisms and intracellular trafficking of phosphorothioate modified oligodeoxynucleotides (P-ODN) might facilitate the use of these compounds for experimental and therapeutic purposes. We addressed these issues by identifying cell surface proteins with which P-ODN specifically interact, studying P-ODN internalization mechanisms, and by tracking internalized P-ODN through the cell using immunochemical and ultrastructural techniques. Chemical cross-linking studies with a biotin-labeled P-ODN (bP-ODN), revealed the existence of five major cell surface P-ODN binding protein groups ranging in size from approximately 20-143 kD. Binding to these proteins was competitively inhibited with unlabeled P-ODN, but not free biotin, suggesting specificity of the interactions. Additional experiments suggested that binding proteins likely exist as single chain structures, and that carbohydrate moieties may play a role in P-ODN binding. Uptake studies with 35S-labeled P-ODN revealed that endocytosis, mediated by a receptor-like mechanism, predominated at P-ODN concentrations < 1 microM, whereas fluid-phase endocytosis prevailed at higher concentrations. Cell fractionation and ultrastructural analysis demonstrated the presence of ODN in clathrin coated pits, and in vesicular structures consistent with endosomes and lysosomes. Labeled ODN were also found in significant amounts in the nucleus, while none was associated with ribosomes, or ribosomes associated with rough endoplasmic reticulum (ER). Since nuclear uptake was not blocked by wheat germ agglutinin or concanavalin A, a nucleoporin independent, perhaps diffusion driven, import process is suggested. These data imply that antisense DNA may exert their effect in the nucleus. They also suggest rational ways to design ODN which might increase their efficiency.
Biological Transport↗
Electron microscopic visualization of insulin translocation into the cytoplasm and nuclei of intact H35 hepatoma cells using covalently linked Nanogold-insulin.
Insulin affects numerous metabolic processes as well as nuclear events such as gene transcription. Our previous ultrastructural and biochemical studies demonstrated insulin accumulation in nuclei of cultured and rapidly proliferating cells, and biochemical evidence suggested that insulin entered the cell cytoplasm before accumulating in the nucleus. The present study was undertaken to develop a covalently linked electron-dense insulin complex that could be used to visualize the intracellular translocation of insulin and confirm that insulin enters the cytoplasm of cells. Insulin was cross-linked to 1.4-nm diameter Nanogold particles. The complex binds to the plasma membrane insulin receptor, is biologically active, and is degraded by cellular insulin-degradative enzymes. Ultrastructural analysis after silver intensification of the gold particles confirmed that insulin internalization culminates in the translocation of some internalized insulin to the cytoplasm and nuclei. When cytoplasmic insulin-degrading enzyme (IDE) activity was inhibited with 1,10-phenanthroline, an increase in the number of cytoplasmic and nuclear Nanogold-insulin particles was observed. The results of this and previous studies suggest that 1) the translocation of insulin to the cytoplasm, 2) the regulation of insulin degradation in the cytoplasm by IDE, 3) the possible interaction of insulin with cytoplasmic proteins other than IDE, and 4) the subsequent accumulation of intact insulin or insulin complexed with cytoplasmic proteins in nuclei may play a role in insulin's regulation of gene transcription and cell proliferation.
Adipose Tissue↗
Risk factors for clozapine discontinuation among 805 patients in the VA hospital system.
The goal of this study was to determine if demographic or clinical factors collected at baseline on patients treated with clozapine would increase the risk of having clozapine discontinued for (a) lack of response, (b) side effects, (c) noncompliance, (d) concomitant illness, or (e) death. The subjects were 805 patients treated with clozapine at 96 Department of Veterans Affairs Hospital System facilities. Multiple logistic regression was used to determine if any of the baseline variables predisposed patients to discontinuation from treatment. Factors which were studied include age, race, history of inadequate response to traditional neuroleptics, history of substance abuse, and DSM-III-R Axis I diagnosis. Of the 805 patients started on clozapine 167 (20.7%) were discontinued from treatment. The only significant variable in the logistic regression model was race. This study finds that African American patients are more likely to have clozapine discontinued than non-African American patients, and there is a trend for prior history of inadequate response to traditional neuroleptics to predict clozapine discontinuation. We found no effect of substance abuse or dependence, diagnosis, or age on outcome in the overall patient group. In a post hoc analysis the African American patients had a significantly lower baseline white blood count than the non-African American patients, which could have explained the difference in clozapine discontinuation. The findings of this study support further investigation into the causes of ethnic differences in treatment outcome with clozapine.
Adult↗
Using oligonucleotide probe arrays to access genetic diversity.
As the Human Genome Project and related efforts identify and determine the DNA sequences of human genes, it is important that highly reliable and efficient mechanisms are found to access individual genetic variation. It is only through a greater understanding of genetic diversity that the true benefit of the Human Genome Project will be realized. One approach, hybridization to high-density arrays of oligonucleotides, is a fast and effective means of accessing this genetic variation. Light-directed chemical synthesis has been used to generate miniaturized, high-density arrays of oligonucleotide probes. Application-specific oligonucleotide probe array designs have been developed for the rapid screening of characterized genes. Dedicated instrumentation and software have been developed for array hybridization, fluorescence detection and data acquisition and analysis. In a specific and challenging application, oligonucleotide probe arrays have been used to screen the reverse transcriptase and protease genes of the highly polymorphic HIV-1 genome to explore genetic diversity and detect mutations conferring resistance to antiviral drugs. Results from this application strongly suggest that oligonucleotide probe arrays will be a powerful tool for rapid investigations in sequence checking, pathogen detection, expression monitoring and DNA molecular recognition.
Base Sequence↗
Current role of intravenous gammaglobulin.
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Humans↗
Interrelationship of prolactin and its receptor in carcinoma of colon and rectum: a preliminary report.
The prolactin receptors (PRLR) were correlated with circulating prolactin and various clinicopathologic parameters to investigate its prognostic value in patients with colorectal cancer. The prolactin (by radioimmunoassay) and its receptors (by radioligand method) were estimated in a total of 71 male patients with colorectal cancer enrolled at the Gujarat Cancer and Research Institute, Ahmedabad. The patients were followed for a period of 3 years. We have observed that 51% colorectal tumors were PRLR+. Significant correlation was not observed between presence/absence of PRLR and clinicopathologic variables. Dukes' D patients were lost to follow-up after 2-3 months; therefore, the results of prognostic significance were analysed only in patients with Dukes' A, B, and C (N = 64). Statistically significant difference in overall survival was not observed when the patients were subgrouped according to the presence/absence of PRLR and according to the cutoff level (i.e., 2%). PRLR+ hyperprolactinemic (Prolactin > 20.0 ng/ml plasma) patients had better overall survival than that of patients with PRLR- hyperprolactinemia, although the difference was statistically nonsignificant. However, PRLR- hyperprolactinemia patients had a more unfavourable prognosis than that of their counterparts. A similar trend was observed in patients with Dukes' B and C disease. Our preliminary study suggests an unequivocal finding, that PRLR- with concomitant hyperprolactinemia probably characterises a subgroup of patients with aggressive colorectal cancer.
Adult↗
Inhaled nitric oxide in congenital diaphragmatic hernia.
Pulmonary hypertension is a major complication of congenital diaphragmatic hernia (CDH). Inhaled nitric oxide (NO) is a selective pulmonary vasodilator because it produces vasodilatation of the pulmonary vasculature without systemic hypotension. In experimental and clinical studies, inhaled NO ameliorates pulmonary hypertension and improves gas exchange. The goal of the present study was to determine the extent to which infants with CDH respond to inhaled NO. Four newborn infants with CDH complicated by severe respiratory insufficiency and right-to-left shunting received inhaled NO. In three patients, postductal oxygenation improved in response to small concentrations of NO (5 to 10 ppm); two received NO after operative repair, and the third both before and after repair. However, tachyphylaxis developed in all cases within 1 to 6 days. A fourth patient received inhaled NO in an attempt at weaning from ECMO. He did not respond, remaining hypoxic despite 80 ppm NO, and continued to require ECMO. In the three patients who responded to inhaled NO, plasma nitrites and nitrates (stable oxidative end products of NO) accumulated over time, but not in the patient who did not respond. The accumulation of nitrite and nitrate in plasma may reflect alveolar-capillary NO absorption, and may identify patients who will respond to continued inhaled NO. Methemoglobin remained below 1.9% in all four babies. Selected infants with CDH may respond to NO, but the benefit may be temporary.
Administration, Inhalation↗