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Biomedical subjects

K Gupta

Publications and source records attributed to K Gupta.

At least 55 records · Page 3Linked to original sources
PubMed2000

Bradykinin-induced airway constriction in guinea-pigs: role of leukotriene D(4).

Tachykinins (TK) have been implicated in both bradykinin-(BK) and hyperpnea-induced broncho-constriction (HIB) in the guinea-pig. However, TKs appear to have an indirect effect in HIB by releasing leukotriene (LT)D(4). We postulated that BK may cause bronchoconstriction through a cascade involving TK and LTD(4). We examined the role of TK and LTD(4)in BK-induced bronchoconstriction in ventilated Hartley guinea-pigs. Respiratory resistance (R(rs)) was monitored for 2 h following insufflation of BK (150 nM). Animals were pretreated with propranolol, then with either neurokinin (NK)1 (CP-99,994)+NK2 (SR-48,968) receptor antagonists or pranlukast (90 microg or 900 microg), an LTD(4)antagonist. Control animals received no pretreatment. BK-induced bronchoconstriction was significantly lower in NK1/NK2 (128%+/-6% baseline R(rs)SEM) and pranlukast (90 microg; 205+/-22, 900 microg; 169+/-20) animals compared to controls (284+/-22), P<0.0001 ANOVA. Bile from control and saline challenged animals was analysed for LTD(4)by HPLC and radio-immunoassay. However, LTD(4)excretion rate showed no significant difference over a 2-h collection period following insufflation of either BK or saline, respectively; baseline =2.5 pmol/h+/-0.6 SEM vs. 2.3+/-0.2, 0-1 h=2.8+/-0.7 vs. 2.0+/-0.6, 1-2 h=2.3+/-0.6 vs. 1.7+/-0.7. We conclude that BK-induced bronchoconstriction is mediated in part through the release of both TK and LTD(4), but the latter is released in insufficient quantities to be detectable by biliary analysis.

Animals↗
PubMed2000

Anaesthesia and juvenile Huntington's disease.

Juvenile Huntington's Disease (JHD) is an involuntary movement disorder that comprises both neurological and psychiatric symptoms. Whilst it has many similarities to Huntington's Disease, it is regarded as a separate clinical entity. The anaesthetic plan should be based on careful assessment of the important issues, including the risk of regurgitation and pulmonary aspiration, possible associated autonomic neuropathy, poor respiratory function and the avoidance of precipitating convulsions and clonic spasms. We describe the management of a 12-year-old girl with JHD scheduled for gastroscopy under general anaesthesia necessitating the use of suxamethonium. We suggest an alternative mechanism for the delayed recovery seen in our patient and in other adult case reports.

Anesthesia, General↗
PubMed2000

Effects of contraceptive method on the vaginal microbial flora: a prospective evaluation.

A prospective evaluation of 331 university women who were initiating use of oral contraceptive pills (OCPs), a cervical cap, diaphragm-spermicide, or other spermicidal methods was done to assess the effects of commonly used contraceptive methods on the vaginal flora. Vaginal introital cultures were performed at baseline and then weekly for 1 month. The prevalence of Escherichia coli vaginal colonization and of abnormal vaginal Gram stain scores (Nugent criteria) increased significantly among women using a cervical cap or diaphragm-spermicide but not among women using OCPs. Women with E. coli colonization were significantly more likely to have an abnormal Nugent score and an absence of lactobacilli. In a multivariate model, use of spermicidal contraception in the preceding week was associated with an abnormal Nugent score and with colonization with E. coli, Enterococcus species, and anaerobic gram-negative rods. Thus, spermicidal methods of contraception are associated with alterations of the vaginal microflora that consequently may predispose women to genitourinary infections.

Adolescent↗
PubMed2000

A human nuclear shuttling protein that interacts with human immunodeficiency virus type 1 matrix is packaged into virions.

Active nuclear import of the human immunodeficiency virus type 1 (HIV-1) preintegration complex (PIC) is essential for the productive infection of nondividing cells. Nuclear import of the PIC is mediated by the HIV-1 matrix protein, which also plays several critical roles during viral entry and possibly during virion production facilitating the export of Pr55(Gag) and genomic RNA. Using a yeast two-hybrid screen, we identified a novel human virion-associated matrix-interacting protein (VAN) that is highly conserved in vertebrates and expressed in most human tissues. Its expression is upregulated upon activation of CD4(+) T cells. VAN is efficiently incorporated into HIV-1 virions and, like matrix, shuttles between the nucleus and cytoplasm. Furthermore, overexpression of VAN significantly inhibits HIV-1 replication in tissue culture. We propose that VAN regulates matrix nuclear localization and, by extension, both nuclear import of the PIC and export of Pr55(Gag) and viral genomic RNA during virion production. Our data suggest that this regulatory mechanism reflects a more global process for regulation of nucleocytoplasmic transport.

Acquired Immunodeficiency Syndrome↗
PubMed1999

Mmip-2, a novel RING finger protein that interacts with mad members of the Myc oncoprotein network.

Mad proteins are basic-helix-loop-helix-leucine zipper (bHLH-ZIP)-containing members of the myc oncoprotein network. They interact with the bHLH-ZIP protein max, compete for the same DNA binding sites as myc-max heterodimers and down-regulate myc-responsive genes. Using the bHLH-ZIP domain of mad1 as a yeast two-hybrid 'bait', we identified Mmip-2, a novel RING finger protein that interacts with all mad members, but weakly or not at all with c-myc, max or unrelated bHLH or bZIP proteins. The mad1-Mmip-2 interaction is mediated by the ZIP domain in the former protein and by at least two regions in the latter which do not include the RING finger. Mmip-2 can disrupt max-mad DNA binding and can reverse the suppressive effects of mad proteins on c-myc-responsive target genes and on c-myc + ras-mediated focus formation in fibroblasts. Tagging with spectral variants of green fluorescent protein showed that Mmip-2 and mad proteins reside in separate cytoplasmic and nuclear compartments, respectively. When co-expressed, however, the proteins interact and translocate to the cellular compartment occupied by the more abundant protein. These observations suggest a novel way by which Mmip-2 can modulate the transcriptional activity of myc oncoproteins.

3T3 Cells↗
PubMed1999

IP-10 inhibits epidermal growth factor-induced motility by decreasing epidermal growth factor receptor-mediated calpain activity.

During wound healing, fibroblasts are recruited from the surrounding tissue to accomplish repair. The requisite migration and proliferation of the fibroblasts is promoted by growth factors including those that activate the epidermal growth factor receptor (EGFR). Counterstimulatory factors in wound fluid are postulated to limit this response; among these factors is the ELR-negative CXC chemokine, interferon inducible protein-10 (IP-10). We report here that IP-10 inhibited EGF- and heparin-binding EGF-like growth factor-induced Hs68 human dermal fibroblast motility in a dose-dependent manner (to 52% and 44%, respectively, at 50 ng/ml IP-10), whereas IP-10 had no effect on either basal or EGFR-mediated mitogenesis (96 +/- 15% at 50 ng/ml). These data demonstrate for the first time a counterstimulatory effect of IP-10 on a specific induced fibroblast response, EGFR-mediated motility. To define the molecular basis of this negative transmodulation of EGFR signaling, we found that IP-10 did not adversely impact receptor or immediate postreceptor signaling as determined by tyrosyl phosphorylation of EGFR and two major downstream effectors phospholipase C-gamma and erk mitogen-activated protein kinases. Morphological studies suggested which biophysical steps may be affected by demonstrating that IP-10 treatment resulted in an elongated cell morphology reminiscent of failure to detach the uropod; in support of this, IP-10 pretreatment inhibited EGF-induced cell detachment. These data suggested that calpain activity may be involved. The cell permeant agent, calpain inhibitor I, limited EGF-induced motility and de-adhesion similarly to IP-10. IP-10 also prevented EGF- induced calpain activation (reduced by 71 +/- 7%). That this inhibition of EGF-induced calpain activity was secondary to IP-10 initiating a cAMP-protein kinase A-calpain cascade is supported by the following evidence: (a) the cell permeant analogue 8-(4-chlorophenylthio)-cAMP (CPT-cAMP) prevented EGF-induced calpain activity and motility; (b) other ELR-negative CXC chemokines, monokine induced by IFN-gamma and platelet factor 4 that also generate cAMP, inhibited EGF-induced cell migration and calpain activation; and (c) the protein kinase A inhibitor Rp-8-Br-cAMPS abrogated IP-10 inhibition of cell migration, cell detachment, and calpain activation. Our findings provide a model by which IP-10 suppresses EGF-induced cell motility by inhibiting EGF-induced detachment of the trailing edges of motile cells.

Amino Acid Sequence↗
PubMed1999

VEGF prevents apoptosis of human microvascular endothelial cells via opposing effects on MAPK/ERK and SAPK/JNK signaling.

Vascular endothelial growth factor (VEGF), an endothelial cell-specific mitogen, promotes endothelial cell survival and angiogenesis. We recently showed that VEGF can support the growth of human dermal microvascular endothelial cells (HDMEC) and human umbilical vein endothelial cells in serum-free medium. Reasoning that VEGF might be modulating apoptotic signal transduction pathways, we examined mechanisms involved in the anti-apoptotic effect of VEGF on starvation- and ceramide-induced apoptosis in HDMEC. We observed that VEGF ameliorated the time-dependent increase in apoptosis, as demonstrated by morphologic observations, TUNEL assay, and DNA fragmentation. On the other hand, basic fibroblast growth factor only partially prevented apoptosis in serum-starved HDMEC; platelet-derived growth factor-BB was completely ineffective. VEGF activated the phosphorylation of extracellular signal regulated kinase (ERK)1 (p44 mitogen-activated protein kinase; MAPK) and ERK2 (p42 MAPK) in a time- and concentration-dependent manner. Both the VEGF-induced activation and its anti-apoptotic effect were prevented by the specific MAPK/ERK inhibitor PD98059. The presence of VEGF also inhibited the sustained activation of stress-activated protein kinase/c-jun-NH2-kinase (SAPK/JNK) caused by serum starvation and ceramide treatment. Activation of the MAPK pathway together with inhibition of SAPK/JNK activity by VEGF appears to be a key event in determining whether an endothelial cell survives or undergoes programmed cell death.

Apoptosis↗
PubMed1999

Increasing prevalence of antimicrobial resistance among uropathogens causing acute uncomplicated cystitis in women.

CONTEXT: Guidelines for the management of acute uncomplicated cystitis in women that recommend empirical therapy in properly selected patients rely on the predictability of the agents causing cystitis and knowledge of their antimicrobial susceptibility patterns. OBJECTIVE: To assess the prevalence of and trends in antimicrobial resistance among uropathogens causing well-defined episodes of acute uncomplicated cystitis in a large population of women. DESIGN: Cross-sectional survey of antimicrobial susceptibilities of urine isolates collected during a 5-year period (January, May, and September 1992-1996). SETTING: Health maintenance organization. PATIENTS: Women aged 18 to 50 years with an outpatient diagnosis of acute cystitis. MAIN OUTCOME MEASURES: Proportion of uropathogens demonstrating in vitro resistance to selected antimicrobials; trends in resistance over the 5-year study period. RESULTS: Escherichia coli and Staphylococcus saprophyticus were the most common uropathogens, accounting for 90% of the 4342 urine isolates studied. The prevalence of resistance among E coli and all isolates combined was more than 20% for ampicillin, cephalothin, and sulfamethoxazole in each year studied. The prevalence of resistance to trimethoprim and trimethoprim-sulfamethoxazole rose from more than 9% in 1992 to more than 18% in 1996 among E coli, and from 8% to 16% among all isolates combined. There was a statistically significant increasing linear trend in the prevalence of resistance from 1992 to 1996 among E coli and all isolates combined to ampicillin (P<.002), and to cephalothin, trimethoprim, and trimethoprim-sulfamethoxazole (P<.001). In contrast, the prevalence of resistance to nitrofurantoin, gentamicin, and ciprofloxacin hydrochloride was 0% to 2% among E coli and less than 10% among all isolates combined, and did not change significantly during the 5-year period. CONCLUSIONS: While the prevalence of resistance to trimethoprim-sulfamethoxazole, ampicillin, and cephalothin increased significantly among uropathogens causing acute cystitis, resistance to nitrofurantoin and ciprofloxacin remained infrequent. These in vitro susceptibility patterns should be considered along with other factors, such as efficacy, cost, and cost-effectiveness in selecting empirical therapy for acute uncomplicated cystitis in women.

Acute Disease↗
PubMed1999

Mechanism of interaction of thrombospondin with human endothelium and inhibition of sickle erythrocyte adhesion to human endothelial cells by heparin.

Thrombospondin (TSP) mediates sickle erythrocyte adhesion to endothelium, but the mechanism remains unknown. Since TSP is comprised of heterogeneously distinct domains, this adhesion may depend on the interaction of specific regions of TSP with different cell surface receptors. To examine the mechanisms of interaction of TSP with human umbilical vein endothelial cells (HUVEC), we performed binding studies using soluble [125I]TSP. Our data showed that (i) monoclonal antibodies (MoAbs) against cell surface heparan sulfate (HS) or the heparin-binding domain of TSP, or cleavage of HS on HUVEC by heparitinase reduced TSP binding by 28-40%, (ii) the RGD peptide or MoAbs against integrin alpha v beta 3 or the calcium binding region of TSP inhibited binding by 18-28%, and (iii) a MoAb against the cell-binding domain of TSP inhibited binding by 36%. Unmodified heparin inhibited the binding of TSP to endothelial cells by 70% and did so far more effectively than selectively desulfated heparins, HS or chondroitin sulfate. Heparin inhibited TSP binding to HUVEC at much lower concentrations than were required to inhibit TSP binding to sickle erythrocytes. Unmodified heparin effectively inhibited the TSP-mediated adhesion of sickle erythrocytes to HUVEC. These data imply that cell surface HS-mediated mechanisms play a key role in TSP-mediated sickle erythrocyte adhesion to endothelium, and heparin may be of use for inhibition of this adhesion.

Anemia, Sickle Cell↗
PubMed1999

Cardiac involvement in limited systemic sclerosis: non-invasive assessment in asymptomatic patients.

Nineteen patients with limited systemic sclerosis (SSc) and without any cardiac symptoms were evaluated non-invasively for silent cardiac involvement using electrocardiography; M-mode, two-dimensional and Doppler echocardiography, and resting and post exercise radionuclide ventriculography. Left anterior hemiblock and mild pericardial effusion were seen in two patients. The interventricular septal thickness and left ventricular posterior wall thickness were greater in patients compared with controls. Patients with limited SSc also exhibited low early diastolic filling velocities and a low early diastolic atrial filling ratio. However, these values did not correlate with the age of the patient or disease duration. Eight patients (42.1%) were found to have cardiac dysfunction, of which four had combined systolic and diastolic dysfunction. Isolated systolic and diastolic dysfunction was seen in three patients and one patient, respectively. The age and disease duration in patients with cardiac dysfunction did not differ from patients without cardiac dysfunction. Functional cardiac involvement occurs in a large proportion (42.1%) of patients with limited SSc, and can be easily picked up by non-invasive methods such as echocardiography and radionuclide ventriculography. The prognostic significance of these findings requires further long term studies.

Adult↗
PubMed1999

Posterior C1-C2 transarticular screw fixation in the treatment of displaced type II odontoid fractures in the geriatric population--review of seven cases.

BACKGROUND: Seven geriatric patients presented with displaced Type II odontoid fractures. All patients underwent a posterior C1-C2 transarticular fixation between November 1994 and December 1996. Ages ranged between 63 and 88 years. METHODS: Fractures were treated with placement of bilateral transarticular screws, allowing immediate fixation, except in one patient, for whom only a unilateral screw was used. An autograft interspinous strut was also placed, allowing three-point fixation. Mean follow-up was 10.6 months. RESULTS: Six patients received rigid fixation and developed a stable union. One patient died before any follow-up could be obtained. Two other patients died within 1 year of unrelated causes. The remaining four patients remain active and independent. One intraoperative vertebral artery injury was identified. No clinical sequalae were noted. CONCLUSION: Posterior transarticular screw fixation is a reasonable option in treating these controversial fractures. Seven geriatric patients tolerated this surgery well, and were mobilized early, avoiding complications related to external immobilization.

Aged↗
PubMed1999

IL-1 receptor-type expression in relation to atopy.

BACKGROUND: IL-1 has 2 receptors, type I (IL-1RI) and type II (IL-1RII), which have 2 forms each, membrane (m) and soluble (s). When IL-1 binds to mIL-1RI, the active receptor, an inflammatory response is initiated, which does not occur when IL-1 binds to mIL-1RII, the decoy receptor. Both sIL-1RI and sIL-1RII function as IL-1-mopping mechanisms. We hypothesized that the ratio of active (mIL-1RI) to inactive (mIL-1RII, sIL-1RI, and sIL-1RII) receptors is important in determining the amount of inflammation produced in allergic reactions. OBJECTIVE: Our aim was to compare the concentrations of mIL-1RI and mIL-1RII on cultured PBLs and sIL-1RI, sIL-1RII, and IL-1beta in sera and supernatants of cultured PBMCs from atopic and nonatopic subjects. METHODS: The membrane receptors, soluble receptors, and IL-1beta concentrations were measured by ELISA with specific mAbs. RESULTS: Although there was no difference in the level of serum IL-1beta between the 2 groups, PBMCs from atopic persons spontaneously secreted higher levels of IL-1beta than those from nonatopic donors (P < .05). PBLs from atopic subjects compared with those from nonatopic individuals expressed higher mIL-1RI (P < .0001) and mIL-1RII (P < .05). Levels of both the soluble receptors from both serum (P < .0001) and PBMCs (P < .05) of nonatopic donors were higher than those found in atopic donors. CONCLUSION: This augmentation of mIL-1RI concomitant with a reduction in soluble receptors may be an important contributory factor to the inflammation that occurs with allergen exposure.

Adult↗
PubMed1999

The prevalence of antimicrobial resistance among uropathogens causing acute uncomplicated cystitis in young women.

Four hundred and fifty-two urine isolates from women with acute uncomplicated cystitis and a positive urine culture presenting to a sexually transmitted disease clinic were collected during 1989-1991, and 213 specimens were collected over 1995-1997. The predominant species was Escherichia coli, representing 68% of the isolates; others included Staphylococcus saprophyticus (8%), Group B streptococci (7%), Proteus spp. (6%), Klebsiella spp. (4%) and Enterococcus spp.(3%). More than 10% of the E. coli isolates were resistant to ampicillin, cephalothin, tetracycline and trimethoprim sulfamethoxazole (TMP SMX ) during both study periods, with the greatest increase in resistance to ampicillin and TMP/SMX between the two periods. Six hundred and four urinary tract infection isolates, including 83% E. coli, 7% S. saprophyticus, 3%, Klebsiella spp. 2% Proteus spp., 2% enterococci, 1% Enterobacter spp. and 2% other organisms, were collected from women with acute cystitis attending a university student health service during 1995. Among E. coli isolates, 25% were resistant to ampicillin, 24% to tetracycline and 11%, to TMP SMX. Resistance to fluoroquinolones was essentially absent among gram-negative pathogens. Continued evaluation of susceptibility patterns of pathogens causing acute uncomplicated cystitis to traditional as well as new antimicrobials in well defined populations is necessary to ascertain the optimal empiric therapy.

Acute Disease↗
PubMed1999

Binding and displacement of vascular endothelial growth factor (VEGF) by thrombospondin: effect on human microvascular endothelial cell proliferation and angiogenesis.

Vascular endothelial growth factor (VEGF) is a specific angiogenic factor, and thrombospondin (TSP), is a potent inhibitor of angiogenesis. To better understand the role of TSP as an anti-angiogenic agent, we have identified its specific domains that participate in its anti-angiogenic activity and examined the mechanism of its inhibitory effect on VEGF(165) induced angiogenesis. Exogenously added TSP inhibited VEGF(165) induced angiogenesis (proliferation and tube formation of human dermal microvascular endothelial cells [HDMEC] and neovascular outgrowth from human arterial rings). Although both VEGF(165) and TSP are heparin binding proteins, TSP had a higher affinity for (125)I-heparin than VEGF(165) (K(d1) 4 nM and K(d2) 14 nM for TSP; K(d) 91 nM for VEGF(165)). TSP displaced 36% of (125)I-VEGF(165) from HDMEC and this was comparable to the 27% reduction in (125)I-VEGF(165) binding to HDMEC upon cleavage of cell surface heparan sulfate (HS). About 35% of the mitogenic activity of VEGF(165) was attributable to its heparin binding region. These results indicate that a proportion of the mitogenic activity of VEGF(165) is inhibited by TSP via competition for cell surface HS. Further, (125)I-VEGF(165) bound directly to TSP in a saturable, concentration dependent manner, and heparin modulated this binding. The mAbs to the heparin binding domain to the type 1 and type 3 repeats of TSP inhibited the binding of VEGF(165) to TSP, and also blocked the inhibitory effect of TSP on VEGF(165) induced HDMEC proliferation. We conclude that (i) the anti-angiogenic activity of TSP is localized in its heparin binding domain and type 1 and type 3 repeats (ii) TSP inhibits angiogenesis by at least two separate mechanisms, (a) displacement of VEGF(165) from endothelial cell HS and (b) direct binding to VEGF(165).

Journal Article↗
PubMed1999

Fas ligand expression in the bone marrow in myelodysplastic syndromes correlates with FAB subtype and anemia, and predicts survival.

Increased apoptosis in the bone marrow (BM) may contribute to the cytopenias that occur in myelodysplastic syndromes (MDS). The Fas receptor, Fas ligand (FasL) pathway is a major mechanism of apoptosis. Since hematopoietic progenitors can express the Fas receptor, they may be susceptible to apoptosis induced by FasL-expressing cells. We examined FasL expression in the BM of patients with MDS (n = 50), de novo acute myeloid leukemia (AML; n = 10), AML following prior MDS (n = 6), and normal controls (n = 6). Compared to controls, FasL expression was increased in MDS, and was highest in AML. In MDS, FasL expression was seen in myeloid blasts, erythroblasts, maturing myeloid cells, megakaryocytes and dysplastic cells, whereas in AML, intense expression was seen in the blasts. FasL expression correlated with the FAB subtype groups of MDS, and also correlated directly with the percentage of abnormal metaphases on cytogenetic analysis. The FasL expressed in MDS BM inhibited the growth of clonogenic hematopoietic progenitors. This inhibition could be blocked by a soluble recombinant FasFc protein. In MDS, FasL expression in the initial diagnostic BM was higher in patients who were more anemic, correlated directly with red cell transfusion requirements over the subsequent course of the disease, and was predictive of survival. These studies indicate that FasL expression in MDS is of prognostic significance, and suggest that pharmacological blockade of the Fas-FasL pathway may be of clinical benefit.

Acute Disease↗