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Biomedical subjects

G Gupta

Publications and source records attributed to G Gupta.

At least 37 records · Page 2Linked to original sources
PubMed2001

New developments in affinity chromatography with potential application in the production of biopharmaceuticals.

Affinity chromatography is likely to play an increasingly important role in the purification of pharmaceutical proteins. This review describes new approaches to the design and synthesis of affinity ligands based on the ability to combine knowledge of X-ray crystallographic or NMR structures with defined or combinatorial chemical synthesis. The de novo design process is based on peptidal templates, complementarity to surface exposed residues and mimicking natural biological recognition. Examples of ligands designed to bind specifically to kallikrein, elastase, immunoglobulin G, insulin, alpha(1)-antitrypsin, clotting factor VII and glyco-proteins are given. The exceptional selectivity and stability of these synthetic ligands allows their use in harsh manufacturing environments.

Biopharmaceutics↗
PubMed2001

Pituitary adenylyl cyclase-activating polypeptide stimulates DNA synthesis but delays maturation of oligodendrocyte progenitors.

The neuropeptide pituitary adenylyl cyclase-activating peptide (PACAP) and one of its receptors (PAC(1)) are expressed in embryonic neural tube, where they appear to regulate neurogenesis and patterning. We now show that PAC(1) gene expression is also present in neonatal rats in the ventricular and subventricular zones and in the optic chiasm, areas that are rich in oligodendrocyte (OL) progenitors (OLP). Because actions of PACAP on OLP have not been reported, we examined the effects of PACAP on the proliferation of purified OLP in culture and on myelinogenesis in cerebellar slices. Northern analyses on total RNA from purified glial cell subtypes revealed an abundant 7 kb hybridizing transcript in OLP, which was confirmed to correspond to the PAC(1) receptor by reverse transcription-PCR. The presence of this receptor was also corroborated by radioligand binding and cAMP assay. In cultured OL, receptor density decreased during maturation but was partially counterbalanced by the appearance of sites that bound both PACAP and the related peptide vasoactive intestinal peptide. PACAP increased DNA synthesis in OLP cultures almost twofold and increased the bromodeoxyuridine-labeling index in O4-positive OLP. PACAP treatment also resulted in decreased sulfate incorporation into sulfatide in cultures of differentiating OL. The PACAP effect on sulfatide synthesis was fully reproduced in a cerebellar explant model. These findings indicate that PACAP may act at two stages during OL development to (1) stimulate proliferation and (2) delay maturation and/or myelinogenesis.

Animals↗
PubMed2001

Structure-based design of a bispecific receptor mimic that inhibits T cell responses to a superantigen.

Key surface proteins of pathogens and their toxins bind to the host cell receptors in a manner that is quite different from the way the natural ligands bind to the same receptors and direct normal cellular responses. Here we describe a novel strategy for "non-antibody-based" pathogen countermeasure by targeting the very same "alternative mode of host receptor binding" that the pathogen proteins exploit to cause infection and disease. We have chosen the Staphylococcus enterotoxin B (SEB) superantigen as a model pathogen protein to illustrate the principle and application of our strategy. SEB bypasses the normal route of antigen processing by binding as an intact protein to the complex formed by the MHC class II receptor on the antigen-presenting cell and the T cell receptor. This alternative mode of binding causes massive IL-2 release and T cell proliferation. A normally processed antigen requires all the domains of the receptor complex for its binding, whereas SEB requires only the alpha1 subunit (DRalpha) of the MHC class II receptor and the variable beta subunit (TCRVbeta) of the T cell receptor. This prompted us to design a bispecific chimera, DRalpha-linker-TCRVbeta, that acts as a receptor mimic and prevents the interaction of SEB with its host cell receptors. We have adopted (GSTAPPA)(2) as the linker sequence because it supports synergistic binding of DRalpha and TCRVbeta to SEB and thereby makes DRalpha-(GSTAPPA)(2)-TCRVbeta as effective an SEB binder as the native MHC class II-T cell receptor complex. Finally, we show that DRalpha-(GSTAPPA)(2)-TCRVbeta inhibits SEB-induced IL-2 release and T cell proliferation at nanomolar concentrations.

Amino Acid Sequence↗
PubMed2001

Effect of chlorsulfuron on growth of submerged aquatic macrophyte Potamogeton pectinatus (sago pondweed).

Research has been conducted on the effect of chlorsulfuron on non-target plants but little information is available on its effects on aquatic macrophytes. Potamogeton pectinatus (sago pondweed) is an ecologically important submerged aquatic macrophyte found in freshwater bodies. Many species of wildlife use this plant as a food source. The objective of this study was to measure the phytotoxic effects of chlorsulfuron on sago pondweed. P. pectinatus plants were exposed to chlorsulfuron at 0, 0.25, 0.50, 1.0, or 2.0 ppb, in an environmental growth chamber. Plants exposed to 0.25 ppb chlorsulfuron showed a reduction in length (76%), number of leaves (50%), and number of stems (50%), compared to control plants. A reduction (47%) was also observed in the length of stems produced by plants treated with > or = 0.50 ppb chlorsulfuron. Significant reductions in wet and dry weights, and increased mortality were observed on treatments with > or = 1.0 ppb chlorsulfuron.

Analysis of Variance↗
PubMed2001

Antithrombotic and thrombolytic therapy for ischemic stroke.

Antithrombotic and thrombolytic agents form the cornerstone of stroke prevention and treatment. Large, randomized trials have also highlighted the effectiveness and safety of early and continuous antiplatelet therapy in reducing atherothrombotic stroke recurrence. Aspirin is the antiplatelet treatment standard against which several other antiplatelet agents (ticlopidine, clopidogrel, aspirin-dipyridamole) have been shown to be more effective. The prevention of cardioembolic stroke is best accomplished with oral anticoagulation, barring any contraindications. The thrombolytic agent, rt-PA, improves outcome in ischemic stroke patients treated within 3 hours of onset. The risk-benefit ratio is narrow because of an increased risk for bleeding but studies do not support a higher risk in the geriatric population.

Acute Disease↗
PubMed2001

Cell-specific caspase expression by different neuronal phenotypes in transient retinal ischemia.

Emerging evidence supports an important role for caspases in neuronal death following ischemia-reperfusion injury. This study assessed whether cell specific caspases participate in neuronal degeneration and whether caspase inhibition provides neuroprotection following transient retinal ischemia. We utilized a model of transient global retinal ischemia. The spatial and temporal pattern of the active forms of caspase 1, 2 and 3 expression was determined in retinal neurons following ischemic injury. Double-labeling with cell-specific markers identified which cells were expressing different caspases. In separate experiments, animals received various caspase inhibitors before the induction of ischemia. Sixty minutes of ischemia resulted in a delayed, selective neuronal death of the inner retinal layers at 7 days. Expression of caspase 1 was not detected at any time point. Maximal expression of caspase 2 was found at 24 h primarily in the inner nuclear and ganglion cell layers of the retina and localized to ganglion and amacrine neurons. Caspase 3 also peaked at 24 h in both the inner nuclear and outer nuclear layers and was predominantly expressed in photoreceptor cells and to a lesser extent in amacrine neurons. The pan caspase inhibitor, Boc-aspartyl fmk, or an antisense oligonucleotide inhibitor of caspase 2 led to significant histopathologic and functional improvement (electroretinogram) at 7 days. No protection was found with the caspase 1 selective inhibitor, Y-vad fmk. These observations suggest that ischemia-reperfusion injury activates different caspases depending on the neuronal phenotype in the retina and caspase inhibition leads to both histologic preservation and functional improvement. Caspases 2 and 3 may act in parallel in amacrine neurons following ischemia-reperfusion. These results in the retina may shed light on differential caspase specificity in global cerebral ischemia.

Amino Acid Chloromethyl Ketones↗
PubMed2001

Functional and morphologic comparison of two methods to produce transient retinal ischemia in the rat.

OBJECTIVES: Much of our knowledge of the pathophysiology of retinal ischemic injury is from a multitude of studies that use in vitro or in vivo animal models of retinal ischemia followed by reperfusion. The objective of this study was to compare histopathologic and electrophysiologic (electroretinography) parameters using two different models of transient retinal ischemia: high intraocular pressure (HIOP) and suture ligation of the optic nerve (SL). METHODS: Transient retinal ischemia was induced using the HIOP model or the SL model in the Sprague-Dawley rat for either 30 or 60 minutes. Histopathologic outcome was determined at 1 and 7 days after ischemia. In addition, electroretinography (ERG) was performed at 2 hours, I day, 3 days, and 7 days after ischemia. RESULTS: At 1 and 7 days after 30 minutes of ischemia, there were no significant histopathologic abnormalities in the retina with either model, except for a slight decrease of the cell count in the ganglion cell layer (GCL) with the SL method. After 60 minutes of ischemia, there was significant thinning of the inner retina. There was a significant early dropout of cells at 1 day in the inner nuclear layer (INL) in the HIOP method compared to the SL method where the dropout was delayed and gradually progressive. Dropout of cells in the GCL was early (I day) and gradually progressive in both models but more severe in HIOP than SL. There was a significant decrease in the ERG b-wave amplitudes as early as 2 hours after both 30 and 60 minutes of ischemia compared to preischemic baselines. CONCLUSIONS: The degree of retinal injury after transient retinal ischemia was more severe at 1 day after reperfusion in the HIOP method compared to the SL method but was similar at 7 days in both models. Furthermore, our data suggests that functional assessment of ischemic damage by electroretinography may be a more sensitive parameter than conventional histopathologic quantification. The timing of either measurement relative to the ischemic stimulus is critical because histologic measurements performed too early after ischemia may underestimate the degree of injury.

Animals↗
PubMed2001

Current concepts in HIV pathogenesis and treatment.

Over the past several years, great strides have been taken in the understanding and treatment of the human immunodeficiency virus. Death rates due to HIV have declined significantly since the introduction of protease inhibitors. Despite the advances in the field, health practitioners are still quite limited in their ability to curb this disease: 40,000 new HIV infections occur every year in the United States. This article will review the new advances in pathogenesis and treatment and discuss the limitations faced in treating the disease.

AIDS Vaccines↗
PubMed2000

Fas (CD95/APO-1) plays a role in the pathophysiology of focal cerebral ischemia.

The purpose of this study was to investigate the role of fas antigen, a member of the TNF receptor family, in cell death after focal cerebral ischemia. Focal ischemia was induced in the Sprague-Dawley rat. Evidence for apoptosis was determined by morphology as well as the presence of DNA fragmentation by the end labeling technique (TUNEL). Immunohistochemistry was performed to detect expression of both fas and fas ligand (fasL). In a separate set of experiments, two groups of mice were studied: lpr (that have a loss of function mutation for fas) and wild type. Infarct volume was measured at 24 hr as well as evidence for apoptosis. Twenty-four hours after ischemia, there was evidence for apoptosis based on morphological criteria as well as the TUNEL technique in the rat. Immunohistochemistry demonstrated increased expression of both fas and fasL in the ischemic region, with maximal staining occurring between 24-48 hr for both. Twenty-four hours after ischemia in the mice, there was evidence of apoptosis in both groups, however, the mutant mice (lpr) had significantly smaller infarcts as compared to the wild type. There was no difference in the cerebrovasculature of the two groups of mice. These data support the hypothesis that apoptosis plays a role in the pathophysiology of focal cerebral ischemia. Furthermore, these data suggest that fas-mediated apoptosis contributes to this process.

Animals↗
PubMed2000

Effective targeting of tumor vasculature by the angiogenesis inhibitors vasostatin and interleukin-12.

Solid tumors are dependent on preexisting vasculature and neovascularization for their growth. Successful cancer therapies targeting the tumor vasculature would be expected to block the existing tumor blood supply and to prevent tumor neovascularization. We tested the antitumor activity of experimental therapy with 2 distinct antiangiogenic drugs. Vasostatin inhibits endothelial cell growth and neovascularization, and interleukin-12 (IL-12) targets the tumor vasculature acting through interferon-gamma (IFN-gamma) and the downstream chemokines interferon-inducible protein-10 (IP-10) and monokine induced by IFN-gamma. Individually, vasostatin and IL-12 produced distinct efficacy profiles in trials aimed at reducing tumor growth in athymic mice. In combination, these inhibitors halted the growth of human Burkitt lymphoma, colon carcinoma, and ovarian carcinoma. Thus, cancer therapy that combines distinct inhibitors of angiogenesis is a novel, effective strategy for the experimental treatment of cancer. (Blood. 2000;96:1900-1905)

Angiogenesis Inhibitors↗
PubMed2000

Clinical trial (GUSTO-1 and INJECT) evidence of earlier death for men than women after acute myocardial infarction.

Epidemiologic studies of acute myocardial infarction (AMI) have described gender differences in the time of death after infarction, with greater numbers of men dying before hospitalization than women. However, in controlled, hospital-based clinical trials, women die at higher rates than men. We hypothesized that evidence of a gender difference in the time of death following AMI may be found in controlled studies of hospitalized AMI patients. We performed a retrospective analysis of the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO-1) and International Joint Efficacy Comparison of Thrombolytics (INJECT) trial databases using logistic regression modeling and time-to-death analyses. The age-adjusted female-to-male odds ratio for mortality was 1.4 (95% confidence interval 1.3 to 1.5) in GUSTO-1 and 1.5 (95% confidence interval 1.3 to 1.8) in INJECT. GUSTO-1 showed that among patients dying during the first 24 hours after symptom onset, men died an average of 1.7 hours earlier than women (p<0.001). This difference was due to earlier deaths among men < or =65 years of age. Furthermore, in GUSTO-1, the analysis of time to death in hour increments demonstrated that greater proportions of men died at earlier time points than women and a disproportionate number of early deaths occurred among younger men than among women of any age or older men. In INJECT, where time to death could only be analyzed in 1-day increments, no gender differences were evident. These results raise the possibility that the pattern of earlier death for men in thrombolytic clinical trials represents the continuation of a gender-specific mortality pattern that began before hospitalization. The death of a disproportionate number of men before hospitalization may represent an inherent gender bias for clinical studies enrolling only hospitalized patients. More high-risk men would be excluded from these studies than women because of death before hospitalization. Hence, gender comparisons of in-hospital mortality rates may artificially inflate values for women.

Clinical Trials as Topic↗
PubMed2000

Plasma membrane-adjacent actin filaments, but not microtubules, are essential for both polarization and hyphal tip morphogenesis in Saprolegnia ferax and Neurospora crassa.

The organization and roles of F-actin and microtubules in the maintenance and initiation of hyphal tip growth have been analyzed in Saprolegnia ferax and Neurospora crassa. In hyphae of both species, the apex is depleted of microtubules relative to subapical regions and near-normal morphogenesis occurs in concentrations of nocodazole or MBC which remove microtubules, slow growth, and disrupt nuclear positioning. In contrast, each species contains characteristic tip-high arrays of plasma membrane-adjacent F-actin, whose organization is largely unaltered by the loss of microtubules but disruption of which by latrunculin B disrupts tip morphology. Hyphal initiation and subsequent normal morphogenesis from protoplasts of both species and spores of S. ferax are independent of microtubules, but at least in S. ferax obligatorily involve the formation of F-actin caps adjacent to the hyphal tip plasma membrane. These observations indicate an obligatory role for F-actin in hyphal polarization and tip morphogenesis and only an indirect role for microtubules.

Actins↗
PubMed2000

Anti-leukotrienes in asthma: yet to arrive.

Inflammation plays a predominant role in the pathogenesis of asthma. The leukotrienes (LTs) exert their actions by binding to and activating various receptors. Leukotrienes B4, C4, D4, and E4 have been shown experimentally to play a role in inflammatory mechanisms, producing the pathologic changes seen in asthma. Antileukotrienes represent a new class of anti-asthma drugs with anti-inflammatory role. In asthma management, LT modifiers from the groups of 5 lipoxygenase inhibitor and Cys LT1 receptor antagonists are found useful. LAs are of main use in mild to moderate chronic asthma. Their usefulness is also observed in allergic rhinitis and even in severe chronic cases of asthma which are resistant to steroids. In chronic asthma they are required to be used for prolonged periods with other agents viz. inhaled steroids and beta 2 agonists. These agents are essentially safe. Except for Montelukast, which can be used in children above six years of age, the paediatric use of other agents is yet to be established. LAs are gradually becoming available in increasing number of countries. In India, we have to presumably wait for sometime before these drugs reach the market. The cost of LAs is reasonably high. Thus, India awaits arrival of LAs, may be for good, as more concrete information from various trials will permit us to practice more evidence based medicine.

Anti-Asthmatic Agents↗
PubMed2000

Estimation of cord blood erythropoietin in pre-eclampsia and eclampsia.

OBJECTIVE: The estimation of cord blood erythropoietin in subjects with pre-eclampsia and eclampsia. METHOD: Erythropoietin was measured, using ELISA, in the cord blood of infants born to 83 mothers with pre-eclampsia, and 7 with eclampsia. Another 90 subjects with no evidence of pre-eclampsia or eclampsia were taken as control subjects. Maternal parity, gestational age, blood pressures, 24-h urine protein and Apgar scores of the infants delivered were also noted. RESULT: Cord blood erythropoietin levels were statistically significantly higher (P<0.001) in infants born to mothers with pre-eclampsia and eclampsia. There was a significant positive correlation (P<0.01) between cord blood erythropoietin levels and maternal blood pressure (systolic and diastolic) and albuminuria. A negative correlation (P<0.01) was observed with the birth weights of infants. CONCLUSION: Pre-eclampsia and eclampsia are associated with higher levels of cord blood erythropoietin.

Adult↗
PubMed2000

Hydroa vacciniforme: A clinical and follow-up study of 17 cases.

BACKGROUND: Hydroa vacciniforme (HV) is a rare, sporadic, idiopathic photodermatosis characterized by vesicles and crust formation after sunlight exposure. The lesions typically heal with vacciniform scarring. OBJECTIVE: We identify and review the clinical features and follow-up data of Scottish patients with HV and report on the prevalence of this condition. This is the largest recent study of HV patients from a single center. METHODS: In this retrospective study, patients with HV were identified by means of the diagnostic database from the Photobiology Unit, Dundee. Patients were contacted and details of clinical features, duration of disease, results of investigations, and treatment were recorded. At review, disease progress was assessed. RESULTS: Between 1973 and 1997, 17 patients (9 males and 8 females) with a diagnosis of HV were investigated. Data from 15 patients showed a mean age at onset of 7.9 years (range, 1 to 16 years), with females (mean, 6.7 years; range, 2 to 12 years) having an earlier onset than males (mean, 8.7 years; range, 1 to 16 years). A bimodal age distribution was also identified with onsets between the ages of 1 and 7 years and 12 and 16 years. At review, spontaneous clearing had occurred in 9 patients (60%) with mean duration of disease being 9 years (range, 4 to 17 years). Males had longer disease duration (mean, 11 years; range, 5 to 17 years) than females (mean, 5 years; range, 4 to 7 years). Eight patients (53%) were sensitive in the UVA wave-band on monochromator phototesting, and 6 (40%) experienced papulovesicular lesions on repetitive broad-spectrum UVA irradiation. All patients received broad-spectrum sunscreens with variable results. Of the 5 patients treated with narrow-band UVB (TL-01) phototherapy, 3 reported beneficial results with an increase in tolerance to sunlight exposure and associated reduction in disease severity. CONCLUSION: The estimated prevalence of HV was at least 0.34 cases per 100,000 with an approximately equal sex ratio. Males had a later onset and longer duration of disease than females. Phototesting showed abnormal responses in the UVA wavebands in 53% of cases, whereas 60% of patients treated with prophylactic TL-01 phototherapy found it beneficial.

Adolescent↗
PubMed2000

The trend of nickel allergy from a Scottish tertiary referral centre.

The aims of this study were to analyze the change in trend of allergic contact dermatitis (ACD) from nickel in a single tertiary referral centre. In 1982 and 1997, 800 and 860 patients were patch tested, respectively. The frequency of positive reactions to nickel from our centre was 16% in 1982 and 22% in 1997. In both years, the vast majority of patients developed the eruption below 30 years of age. However, the commonest age of onset in 1982 was in the 11-20 year age group, while in 1997, this was 1 decade later, in the 21-30 year age group. In 1997, we noted a much higher female preponderance (F:M=13:1) than in 1982 (F:M=6:1). There was no change in male prevalence but a slight increase in female prevalence in 1997. The rate of atopy in patients with nickel ACD showed an increase from 23% in 1982 to 33% in 1997. Nickel was thought to be a contributory factor in causing occupational dermatitis in 27% of patients in 1982 and 24% patients in 1997. Of these, hairdressing in 1982 and nursing in 1997 were the commonest occupations. In 1982 and 1997, respectively, 40 (5%) and 37 (4%) patients were positive to nickel alone, while 89 (11%) and 150 (18%) patients showed positive reactions to other allergens in addition to nickel. In both the years, the hands were the main sites of involvement. However, in 1997 there was an increase in the number of patients presenting with face and neck involvement.

Adolescent↗