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Biomedical subjects

N Shah

Publications and source records attributed to N Shah.

At least 19 recordsLinked to original sources
PubMed1992

A brefeldin A-like phenotype is induced by the overexpression of a human ERD-2-like protein, ELP-1.

Brefeldin A (BFA) is a unique drug affecting the molecular mechanisms that regulate membrane traffic and organelle structure. BFA's ability to alter retrograde traffic from the Golgi to the endoplasmic reticulum (ER) led us to ask whether the ERD-2 retrieval receptor, proposed to return escaped ER resident proteins from the Golgi, might either interfere with or mimic the effects of the drug. When either human ERD-2 or a novel human homolog (referred to as ELP-1) is overexpressed in a variety of cell types, the effects are phenotypically indistinguishable from the addition of BFA. These include the redistribution of the Golgi coat protein, beta-COP, to the cytosol, the loss of the Golgi apparatus as a distinct organelle, the mixing of this organelle with the ER, the addition of complex oligosaccharides to resident ER glycoproteins, and the block of anterograde traffic. Thus, these receptors may provide signals that regulate retrograde traffic between the Golgi and the ER.

Amino Acid Sequence↗
PubMed1992

Transplantation of umbilical cord blood after myeloablative therapy: analysis of engraftment.

The possibility that umbilical cord and placental blood from an HLA-identical sibling might produce stable donor-derived lymphohematopoietic engraftment was tested in a patient with juvenile chronic myelogenous leukemia (JCML). After conditioning with high-dose busulfan and cyclophosphamide, cryopreserved umbilical cord blood, containing 0.5 x 10(8) nucleated cells/kg and 2.7 x 10(4) colony forming units-granulocyte, macrophage (CFU-GM)/kg, was infused. A leukocyte count greater than 1,000/microL, absolute neutrophil count (ANC) greater than 500/microL, and platelet count greater than 20,000/microL (untransfused) were observed on days 39, 39, and 47 after transplantation, respectively. Donor cell engraftment was documented in the peripheral blood and bone marrow by cytogenetic analysis, restriction fragment length polymorphism (RFLP), and polymerase chain reaction (PCR) as early as day 21. Furthermore, the donor origin of each lymphohematopoietic lineage (ie, CD5+ T cells, CD19/20+ B cells, CFU-GM, and burst-forming unit-erythrocyte [BFU-E]) was confirmed. On day 200, assays of the peripheral blood and bone marrow showed an abnormal proliferation of CFU-GM at low seeding densities in the absence of exogenous growth factors, as well as a hypersensitivity to granulocyte-macrophage colony-stimulating factor (GM-CSF), both pathophysiologic characteristics of JCML. Recurrent disease was confirmed histologically on day 225. Together, these results demonstrate that umbilical cord blood contains sufficient numbers of hematopoietic stem cells necessary for the engraftment of leukemia patients treated with myeloablative therapy and that the detection of "spontaneous" CFU-GM and hypersensitivity to GM-CSF after treatment is a marker of residual or recurrent disease in patients with JCML.

Base Sequence↗
PubMed1992

Monosomy 7 myeloproliferative disease in children with neurofibromatosis, type 1: epidemiology and molecular analysis.

Loss of constitutional heterozygosity is a common molecular feature of cancers in which inactivation of one or more tumor suppressor genes is thought to contribute to tumorigenesis. Recent evidence suggests that the gene responsible for neurofibromatosis, type 1 (NF-1), belongs to this class of heritable cancer genes. Children with NF-1 show an increased incidence of myeloid leukemia, including juvenile chronic myelogenous leukemia (JCML) and, perhaps, the myeloproliferative syndrome (MPS) associated with bone marrow monosomy 7 (Mo 7). We have investigated five children with Mo 7: three with NF-1 and two others with suggestive evidence of NF-1. Southern blotting experiments performed in four patients showed no loss of heterozygosity in bone marrow specimens using probes linked to the NF-1 locus on the long arm of chromosome 17. Both of our patients with familial NF-1 inherited the disease from their mothers, as did 14 of 19 other cases of myeloid leukemia in children with familial NF-1. Seventeen of these 21 children were boys. Myeloid leukemia developed in 12 boys and four girls who inherited NF-1 from their mothers, and in five boys who inherited the disease from their fathers. Father-to-daughter transmission was not observed. Taken together, the presence of chromosome 7 deletions in the leukemias of children with NF-1, a pattern of inheritance favoring maternal transmission of NF-1, and the marked predilection for boys to develop JCML and Mo 7 suggest a multistep mechanism of oncogenesis in which epigenetic factors might play a role. Further investigation is required to determine if the NF-1 genes in the leukemic bone marrows of these patients have acquired point mutations or small deletions.

Blotting, Southern↗
PubMed1992

Esmolol infusion during nitroprusside-induced hypotension: impact on hemodynamics, ventricular performance, and venous admixture.

The impact of esmolol infusion on hemodynamics, ventricular performance, venous admixture, sympathoadrenal, and renin-angiotensin system responses during sodium nitroprusside (SNP)-induced hypotension was studied in 11 patients undergoing lymph node dissection during general anesthesia with 60% nitrous oxide and fentanyl. Radial arterial and thermistor-tipped pulmonary catheters were employed for hemodynamic monitoring. Arterial and mixed venous blood gas tensions, arterial plasma renin activity (PRA), and plasma catecholamine levels were measured. Derived hemodynamic parameters and venous admixture (Qs/Qt) data were obtained from standard equations. Transesophageal echocardiography (6 patients) was used to assess left ventricular performance using the relationship between end-systolic wall stress (ESWS) and velocity of circumferential shortening (VCFC). After surgical incision, arterial hypotension was induced with SNP alone. Esmolol was infused at each of the following rates in sequence: 200, 300, and 400 micrograms/kg/min. Each esmolol infusion lasted 20 minutes and the SNP dose was adjusted to maintain MAP at 55 to 60 mm Hg. The mean dose of SNP required to induce hypotension was 5.5 micrograms/kg/min +/- 0.5 SE. Compared to prehypotension values, SNP induced significant increases in Qs/Qt and reductions in PaO2, systemic vascular resistance (SVR), and stroke volume index (SVI). Esmolol infusion caused dose-dependent (highest with 400 micrograms/kg/min) reductions in the SNP requirement, heart rate (HR), SVI, Qs/Qt, and PRA, and also led to significant increases in SVR and left ventricular (LV) internal diameter in diastole as well as systole. Furthermore, esmolol infusion was associated with a dose-dependent downward and leftward shift of the ESWS versus VCFC relationship, implying diminished contractility.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic beta-Antagonists↗
PubMed1992

Plasmacytoma of anterior maxilla mimicking periapical cyst.

An unusual case of plasmacytoma mimicking a large periapical cyst in the anterior maxilla is described. Of the involved teeth, 22 was discoloured and had an open, immature apex, a feature strongly suggestive of the lesion being of pulpal origin. The case was treated by a conservative endodontic approach, but failed to show any improvement. Apical surgery comprising complete enucleation of the cystic lesion and extraction of the involved tooth was carried out. The unexpected histopathological finding was a plasmacytoma.

Adult↗
PubMed1992

Fatal disseminated infection caused by Myceliophthora thermophila, a new agent of mycosis: case history and laboratory characteristics.

We report a case of human infection caused by the hyphomycete Myceliophthora thermophila. A 7-year-old male with neurofibromatosis (type 1) was diagnosed in 1987 with acute myeloblastic leukemia associated with the chromosomal abnormality monosomy 7. The patient experienced multiple serious infections over a three-year period before expiring in 1990 while in the end stage of leukemia. Autopsy findings included fungal vegetations of the left atrium, ascending aorta, and pulmonary arteries and fungal invasion of both lungs. Cultures yielded M. thermophila. We believe that this is the first reported fatality caused by M. thermophila.

Child↗
PubMed1992

Bone marrow transplantation of chronic myelogenous leukemia in chronic phase: evaluation of risks and benefits.

PURPOSE: Allogeneic bone marrow transplantation (BMT) is an option for some patients with chronic myelogenous leukemia (CML). We retrospectively evaluated the effect of various risk factors observed at diagnosis and at transplantation on survival, event-free survival (EFS), and relapse after BMT. PATIENTS AND METHODS: Seventy-nine patients with CML in chronic phase (CP) were treated with cyclophosphamide and total body irradiation followed by BMT. Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine (CsA) in most instances or CsA plus the use of lymphocyte-depleted bone marrow (BM). RESULTS: Survival at 4.5 years was 52%. Stratified by age and GVHD prophylaxis, the actuarial survival was 65% (95% confidence interval [CI], 47% to 78%) in patients aged less than 30 years receiving unmanipulated BM, 33% (95% CI, 12% to 56%) in patients greater than or equal to 30 years old receiving unmanipulated BM, and 38% (95% CI, 14% to 63%) in patients greater than or equal to 30 years old receiving lymphocyte-depleted BM. In univariate analysis, patient age (greater than or equal to 30 years) and the use of lymphocyte-depleted BM negatively influenced EFS. When stratified by age and GVHD prophylaxis, however, ABO incompatibility, cytomegalovirus (CMV) seropositivity, and chronic GVHD significantly reduced the probability of EFS. Factors that have been associated with early death in nontransplanted patients (ie, sex, spleen size, blast and platelet counts at presentation) were not predictive of long-term survival outcome after BMT. CONCLUSIONS: The data suggest that (1) BMT should be offered early after diagnosis to all patients with CML in CP who have compatible sibling donors regardless of prognostic factors at presentation, (2) GVHD remains the principal cause of mortality after BMT in patients receiving CsA, and (3) T-cell depletion by the physical separation method of counterflow elutriation (CE) is associated with a significant risk of relapse.

Adolescent↗
PubMed1992

Insulin and IGF1 receptors in a model renal epithelium: receptor localization and characterization.

Insulin and IGF1 stimulate transepithelial Na+ transport in the urinary bladder of the toad Bufo marinus, a model renal epithelium. The signal transduction mechanisms for the natriferic action are unknown. Ultrastructural techniques were used to localize both receptors and ligands in the epithelium. Electron microscopy using gold-labelled anti-insulin or anti-IGF1 receptor antibodies demonstrated the majority of the insulin receptors were associated with the basolateral membrane while IGF1 receptors were found on basolateral and apical membranes. Both insulin and IGF1 receptors were found in endosomes and on the membranes surrounding subapical granules. In intact tissues incubated with iodinated IGF1 or insulin, both ligands were associated with the basolateral membrane. IGF1 was internalized to a greater extent than insulin and only IGF1 accumulated in cell nuclei.

Animals↗
PubMed1992

Relapse of leukemia after bone marrow transplantation: effect of second myeloablative therapy.

Twenty-three patients with recurrent leukemia after bone marrow transplantation (BMT) underwent a second myeloablative therapy followed by second transplant between June 1977 and April 1991. Patients had either acute lymphocytic leukemia (n = 4), acute myelogenous leukemia (n = 7) or chronic myelogenous leukemia (n = 12). The median age was 29 years and the median interval between first and second BMT was 22.6 months. The second preparative therapy consisted of cyclophosphamide (200 mg/kg) and total body irradiation (1200 cGy) in nine patients and busulfan (16 mg/kg) and cyclophosphamide (120-200 mg/kg) with or without etoposide (30-60 mg/kg) in 14 patients. The same sibling donor (three syngeneic, 20 allogeneic) was used for both transplants. All patients demonstrated prompt neutrophil recovery (median 21 days) with donor-derived hematopoiesis documented in 16 of 16 evaluable patients. With a median follow-up of 24 months after second BMT, the survival, event-free survival and probability of remaining in remission at 26 months are 47%, 38% and 76% respectively. Outcome was best in patients with chronic myelogenous leukemia (7/12 survivors) and worst in patients with acute leukemia (2/11 survivors). Thus, the data would suggest that (1) selected patients with recurrent leukemia after BMT can still be cured with myeloablative therapy and second BMT, and (2) further improvements in outcome will be dependent upon the reduction of regimen-related toxicity.

Adolescent↗
PubMed1991

Tyrosine kinase-defective insulin receptors undergo insulin-induced microaggregation but do not concentrate in coated pits.

Biologically active colloid-gold complexes were used to compare ligand-induced microaggregation, redistribution, and internalization of insulin receptors on Rat 1 fibroblasts expressing wild type (HIRc) or tyrosine kinase-defective (HIR A/K1018) human insulin receptors. Insulin-like growth factor I (IGF I) and alpha 2-macroglobulin receptors also were compared. On both cell types, all four unoccupied receptor types occurred predominantly as single receptors. Ligand binding caused receptor microaggregation. Microaggregation of wild type or kinase-defective insulin receptors or IGF I receptors was not different. alpha 2-Macroglobulin receptors formed larger microaggregates. Compared to wild type insulin or IGF I receptors, accumulation of kinase-defective insulin receptor microaggregates in endocytic structures was decreased, and the size of microaggregates in coated pits was significantly smaller. As a result, receptor-mediated internalization of gold-insulin by HIR A/K1018 cells was less than 6% of the cell-associated particles compared to approximately 60% of the particles in HIRc cells. On HIR A/K1018 cells, alpha 2-macroglobulin and IGF I were internalized via coated pits demonstrating that those structures were functional. These results suggest that: 1) ATP binding, receptor autophosphorylation, and activation of receptor kinase activity are not required for receptor microaggregation; 2) receptor microaggregation per se is not sufficient to cause ligand-induced receptor-mediated internalization or the biological effects of insulin; and 3) autophosphorylation of the beta-subunit or activation of the receptor kinase activity is required for the insulin-induced concentration of occupied receptors in coated pits.

Animals↗
PubMed1991

Immunoelectron microscopic demonstration of insulin-stimulated translocation of glucose transporters to the plasma membrane of isolated rat adipocytes and masking of the carboxyl-terminal epitope of intracellular GLUT4.

Polyclonal antibodies to the amino- or carboxyl-terminated peptide sequences of the GLUT4 transporter protein were used in immunoelectron microscopic studies to demonstrate the location and insulin-induced translocation of GLUT4 in intact isolated rat adipocytes. Labeling of untreated adipocytes with the amino-terminal antibody revealed 95% of GLUT4 was intracellular, associated with plasma membrane invaginations or vesicles contiguous with or within 75 nm of the cell membrane. Insulin treatment increased plasma membrane labeling approximately 13-fold, to 52% of the total transporters, and decreased intracellular labeling proportionately. In contrast, labeling of untreated adipocytes with the carboxyl-terminal antibody or with a monoclonal antibody (1F8) that binds to the carboxyl terminus of GLUT4 detected fewer transporters, only approximately 40% of which were intracellular. In insulin-treated cells, plasma membrane labeling increased approximately 20-fold, but the total number of labeled transporters also increased approximately 13-fold. The number of intracellular transporters was not changed. The insulin-induced increase in plasma membrane labeling was reversible. Thus, the vast majority of GLUT4 transporters in untreated adipocytes are intracellular in invaginations or vesicles attached or close to the plasma membrane. Insulin treatment causes translocation of transporters to the plasma membrane, which involves flow of transporters from invaginations to the cell surface and possible fusion of subplasma membrane vesicles with the plasma membrane. Differences in the labeling of intracellular transporters by peptide antibodies suggested the carboxyl-terminal epitope of intracellular transporters was masked. The unmasking of the carboxyl terminus during translocation to the plasma membrane may be part of the mechanism by which insulin stimulates glucose transport in rat adipocytes.

Adipose Tissue↗
PubMed1991

Chromosome 7 abnormalities in children with Down syndrome and preleukemia.

Three children, two boys and one girl, with Down syndrome (DS) who presented with preleukemia and loss of all or part of chromosome 7 were studied. Initial presentation, with cytopenias and less than 25% blasts in the bone marrow, was between 13 and 30 months of age. Progression to acute nonlymphocytic leukemia occurred 1-8 months after initial presentation. The morphologic type was megakaryoblastic in two, and undifferentiated in one. Two children achieved remission with intensive therapy, and one continues in remission off therapy; the other child died in remission of accidental causes. The third child died of respiratory distress and leukemia after no intervention was chosen. These cases represent the first examples of chromosome 7 abnormalities associated with DS and leukemia, and suggest differences from the "monosomy 7" syndrome seen in children without DS.

Child, Preschool↗
PubMed1991

Influence of tryptophan modification upon digestion of antithrombin III by elastase.

Chemical modification of tryptophan residues in antithrombin III by dimethyl (2-hydroxy-5-nitrobenzyl) sulfonium bromide (HNBSB) generates products with similar levels of modification (equivalent to 0.9 mole 2-hydroxy-5-nitrobenzyl [HNB] incorporated/mole of antithrombin III) but with high or low affinity for heparin-Sepharose. Upon digestion with pancreatic or neutrophil elastase the low affinity forms generate a product of molecular weight form (55 kDa) not seen in digests of native antithrombin III or modified forms with high affinity for heparin. When measured as loss of activity the observed rate of digestion of the latter in the absence of heparin was more rapid than that of native antithrombin III. The differences in digestion are considered to be related to conformation at differences between the various forms.

Antithrombin III↗
PubMed1991

Role of potentially charged transmembrane residues in targeting proteins for retention and degradation within the endoplasmic reticulum.

The selective breakdown of newly synthesized proteins retained within the endoplasmic reticulum (ER) is probably mediated by the specific recognition of structural features of protein substrates by components of a degradative system. Within the alpha chain of the multisubunit T-cell antigen receptor (TCR) complex, a transmembrane sequence containing two basic amino acid residues has been shown to act as a determinant for retention and rapid degradation in the ER. We now demonstrate that single basic or acidic amino acid residues can cause targeting for retention and degradation in the ER when placed within the transmembrane domain of an integral membrane protein normally destined for the cell surface. The effect of such potentially charged residues is dependent on their relative position within the transmembrane sequence and on the nature of the amino acid side chains. The phenotypic changes induced by potentially charged transmembrane residues occur without apparent alterations of the global folding or transmembrane topology of the mutant proteins. These observations test the hypothesis that potentially charged residues within transmembrane domains can provide the basis for a motif for ER degradation and explain the selective breakdown of some proteins retained within the ER.

Amino Acid Sequence↗
PubMed1991

Improved detection of hypotension by automated noninvasive blood pressure monitoring.

This study was undertaken to determine whether the use of automated noninvasive blood pressure monitoring altered the frequency of detection of intraoperative hypotension. We retrospectively reviewed 1,861 anesthetic records from a period in 1987, when blood pressure was obtained manually by auscultation. We compared the records from 1987 with 1,716 anesthetic records from 1989, when automated blood pressure monitors were used universally. The incidences of hypotension requiring vasopressor therapy were determined during the two periods and compared using Student's two-tailed t test. The data revealed that the incidence of detected hypotension increased from 2.4 to 5.2% with the use of automated blood pressure monitors (P less than 0.00002). We conclude that at our hospital the use of automated noninvasive blood pressure monitors increases the incidence of detection of intraoperative hypotension as compared with the use of manual blood pressure measurement.

Anesthesia↗
PubMed1991

Serum lipoproteins and apolipoproteins in young normocholesterolaemic, non-diabetic Indian men with myocardial infarction.

Serum total cholesterol, triglycerides, high density lipoprotein cholesterol, low density lipoprotein cholesterol, apolipoprotein A-I and apolipoprotein B were evaluated as potential indicators of the risk of coronary artery disease in young (less than 46 years) normocholesterolaemic, non-diabetic men who had previously sustained a myocardial infarction (n = 50) and in healthy age and sex matched controls (n = 122) with a similar socioeconomic background. Significant differences were observed between patients and controls in the mean concentrations of serum total cholesterol, triglycerides, low density lipoprotein cholesterol, high density lipoprotein cholesterol and apolipoprotein B, as well as in the ratios of total cholesterol to high density lipoprotein cholesterol and apolipoprotein A-I to apolipoprotein B. No significant difference was demonstrated in the concentration of apolipoprotein A-I between the two groups. Stepwise discriminant analysis indicated that apolipoprotein B was the best discriminant between patients and controls. The percentage of exact classification was 74% in patients and 66% in controls. When the patients were compared to a subset of controls (n = 50) matched for age and total cholesterol, significant differences were demonstrated only in the mean concentrations of apolipoprotein B. Discriminant analysis confirmed that the best single discriminating variable was apolipoprotein B. The results therefore indicate that in young normocholesterolaemic, non-diabetic Indian men with myocardial infarction, apolipoprotein B is superior to other lipid parameters studied, as a marker for coronary artery disease.

Adult↗
PubMed1991

Delayed haemolytic transfusion reactions in patients with sickle cell disease.

We describe two cases which illustrate the difficult diagnostic and therapeutic problems posed by delayed haemolytic transfusion reactions in patients with sickle-cell disease. The cases emphasize the need for meticulous phenotypic and serological assessment of sickle-cell patients prior to transfusion therapy.

Adolescent↗