Biomedical subjects
Publications and source records attributed to R Singh.
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The mechanism by which estrogens protect against atherosclerosis is not known. We evaluated in vivo whether there is a gender difference in monocyte adhesion and subendothelial migration in hypercholesterolemic rabbits and whether any gender differences observed are due to estradiol. Monocyte adhesion and subendothelial migration were assessed in a blinded fashion by analyzing a standardized segment of aorta using a scanning electron microscope. We also assessed whether estradiol modulates induction of vascular cell adhesion molecule-1 (VCAM-1) protein using Western blot and flow cytometric analyses. We observed that male rabbits develop more monocyte adhesion and subendothelial migration than do female rabbits during hypercholesterolemia. We also observed that oophorectomized rabbits given physiological estradiol supplementation demonstrate fewer adherent and subendothelial monocytes than do oophorectomized rabbits given placebo. VCAM-1 protein expression was increased in aortae obtained from hypercholesterolemic, oophorectomized animals supplemented with placebo, and this increase was attenuated by estradiol. Finally, in cultured rabbit aortic endothelial cells stimulated with lysophosphatidylcholine, we observed an increase in VCAM-1 protein that was inhibited in a concentration-dependent fashion by estradiol. We have demonstrated in vivo that there is a gender difference in monocyte adhesion to endothelial cells and transendothelial migration after hypercholesterolemia and that this gender difference is due in part to estradiol. Our results also suggest that estradiol inhibits monocyte adhesion by inhibiting expression of VCAM-1.
The neutrophil-specific G-protein-coupled chemokine receptors, CXCR1 and CXCR2, bind with high affinity to the potent chemoattractant interleukin-8 (IL-8). The mechanisms of IL-8 receptor regulation are not well defined, although previous studies have suggested a process of ligand-promoted internalization as a putative regulatory pathway. Herein, we provide evidence for two distinct processes of CXCR1 and CXCR2 regulation. Confocal microscopy data showed a redistribution of CXCR1 expression from the cell surface of neutrophils to internal compartments after stimulation with IL-8, whereas stimulation with bacterial lipopolysaccharide (LPS) or tumor necrosis factor-alpha (TNF-alpha) did not induce CXCR1 internalization but instead mediated a significant loss of membrane-proximal CXCR1 staining intensity. To investigate whether proteolytic cleavage was the mechanism responsible for LPS- and TNF-alpha-induced downmodulation of IL-8 receptors, we tested a panel of proteinase inhibitors. The downmodulation of CXCR1 and CXCR2 by LPS and TNF-alpha was most dramatically inhibited by metalloproteinase inhibitors; 1, 10-phenanthroline and EDTA significantly attenuated LPS- and TNF-alpha-induced loss of CXCR1 and CXCR2 cell surface expression. Metalloproteinase inhibitors also blocked the release of CXCR1 cleavage fragments into the cell supernatants of LPS- and TNF-alpha-stimulated neutrophils. In addition, while treatment of neutrophils with LPS and TNF-alpha inhibited IL-8 receptor-mediated calcium mobilization and IL-8-directed neutrophil chemotaxis, both 1, 10-phenanthroline and EDTA blocked these inhibitory processes. In contrast, metalloproteinase inhibitors did not affect IL-8-mediated downmodulation of CXCR1 and CXCR2 cell surface expression or receptor signaling. Thus, these findings may provide further insight into the mechanisms of leukocyte regulation during immunologic and inflammatory responses.
Behavioral and neuropsychological studies suggest that upright and inverted face stimuli are processed by computationally and anatomically distinct systems. Specifically, inverted faces seem to be addressed by general object perception systems, avoiding face-specific processes. We tested this model by examining the fMRI signal response of a functionally defined fusiform face area and bilateral object-responsive cortical areas during the perception of upright and inverted stimuli (faces and cars). While inversion of face stimuli had no effect upon the magnitude of responses in the fusiform face area, inverted faces evoked greater neural responses compared to upright faces within object regions. This finding supports the assertion that object areas are involved to a greater degree in the perception of inverted vs upright faces.
Based on the hypothesis that genetic modification of freshly isolated alveolar macrophages (AM) with the granulocyte-macrophage colony-stimulating factor (GM-CSF) cDNA would induce AM to proliferate, this study focuses on the ability of adenoviral (Ad) vectors to transfer and efficiently express the murine (m) GM-CSF cDNA in murine AM with consequent expansion in the number of AM in vitro and in vivo. To demonstrate that an Ad vector can effectively transfer and express genes in AM, murine AM recovered by bronchoalveolar lavage from the lung of Balb/c mice were infected with an Ad vector coding for green fluorescent protein (GFP) in vitro and expressed GFP in a dose-dependent fashion. Infection of AM with an Ad vector containing an expression cassette coding for mGM-CSF led to GM-CSF expression and to AM proliferation in vitro. When AM infected with AdGFP were returned to the respiratory tract of syngeneic recipient mice, GFP-expressing cells could still be recovered by bronchoalveolar lavage 2 weeks later. In vitro infection of AM with AdmGM-CSF and subsequent transplantation of the genetically modified AM to the lungs of syngeneic recipients led to GM-CSF expression in vivo. Strikingly, the AM recovered by lavage 5 weeks after transplantation demonstrated an increased rate of proliferation, and the total number of alveolar macrophages was 1. 9-fold greater than controls. Importantly, the increase in the numbers of AM was selective (ie, other inflammatory cell numbers were unchanged), and there was no modification to the lung architecture. Thus, it is feasible to genetically modify AM with Ad vectors and to use this strategy to modify the behavior of AM in vivo. Based on the importance of AM in the primary defense of the respiratory epithelial surface, this strategy may be useful in enhancing pulmonary defenses in immunodeficiency states.
We examined the phenotypic variation and clinical genetics in nine families with generalized epilepsy with febrile seizures plus (GEFS+). This genetic epilepsy syndrome with heterogeneous phenotypes was hitherto described in only one family. We obtained genealogical information on 799 individuals and conducted detailed evaluation of 272 individuals. Ninety-one individuals had a history of seizures and 63 had epilepsy consistent with the GEFS+ syndrome. Epilepsy phenotypes were febrile seizures (FS) in 31, febrile seizures plus (FS+) in 15, FS+ with other seizure types (atonic, myoclonic, absence, or complex partial) in 8, and myoclonic-astatic epilepsy in 9 individuals. Inheritance was autosomal dominant with approximately 60% penetrance. This study confirms and expands the spectrum of GEFS+ and provides new insights into the phenotypic relationships and genetics of FS and the generalized epilepsies of childhood. Moreover, the ability to identify large families with this newly recognized common, childhood-onset, generalized genetic epilepsy syndrome suggests that it should be a prime target for attempts to identify genes relevant to FS and generalized epilepsy.
High altitude stress leads to lipid peroxidation and free radical formation which results in cell membrane damage in organs and tissues, and associated mountain diseases. This paper discusses the changes in biochemical parameters and antibody response on feeding glutamate to male albino Sprague Dawley rats under hypoxic stress. Exposure of rats to simulated hypoxia at 7576 m, for 6 h daily for 5 consecutive days, in an animal decompression chamber at 32 +/- 2 degrees C resulted in an increase in plasma malondialdehyde level with a concomitant decrease in blood glutathione (reduced) level. Supplementation of glutamate orally at an optimal dose (27 mg/kg body weight) in male albino rats under hypoxia enhanced glutathione level and decreased malondialdehyde concentration significantly. Glutamate feeding improved total plasma protein and glucose levels under hypoxia. The activities of serum glutamate oxaloacetate transaminase (SGOT) and serum glutamate pyruvate transaminase (SGPT) and the urea level remained elevated on glutamate supplementation under hypoxia. Glutamate supplementation increased the humoral response against sheep red blood cells (antibody titre). These results indicate a possible utility of glutamate in the amelioration of hypoxia-induced oxidative stress.
Urinary excretion of galactitol was determined in 95 normals (N/N), 67 galactosemic (G/G), and 39 compound heterozygotes for the Duarte and galactosemia genotype (D/G). Galactitol excretion is age-dependent in both normal individuals and patients with classic galactosemia on lactose-restricted diets. In galactosemic patients who are homozygous for the Q188R mutation, urinary galactitol levels were fivefold to 10-fold higher than those of normal subjects of comparable age. All but a few patients with classic galactosemia with the Q188R mutation and another mutant G allele had urinary excretion comparable to the Q188R homozygous patients. African-American galactosemic patients with the S135L mutation of the galactose-1-phosphate uridyltransferase (GALT) gene also excreted abnormal quantities of galactitol. Most subjects with a Duarte allele and a G allele excrete normal amounts of the sugar alcohol. There is a correlation between galactitol excretion and red blood cell (RBC) galactose-1-phosphate (gal-1-P). Plasma galactitol was also elevated in galactosemic patients (3.4 to 23.2 micromol/L; undetectable in normal individuals). In contrast to the decrease in urinary galactitol with age, plasma levels remain in a narrow concentration range with no significant difference with age. Urine and plasma galactitol distinguish galactosemic patients from normals. In addition, urinary galactitol excretion may be an important parameter for the assessment of steady-state galactose metabolism in galactosemia.
PURPOSE: To evaluate the results of phacoemulsification in eyes with posterior polar developmental cataract and to appraise the strategy for surgical management. SETTING: Iladevi Cataract & IOL Research Centre, Raghudeep Eye Clinic, Ahmedabad, India. METHOD: This prospective study comprised 25 consecutive patients. All surgeries were performed by 1 surgeon. Endophacoemulsification was carried out after hydrodelineation. Hydrodissection or rotation was not attempted. A 2-port vitrectomy was performed when necessary. RESULTS: Mean follow-up was 13.72 months (range 7 to 22 months). Nine patients (36%) developed posterior capsule rupture and 8 (32%) revealed plaques. An intraocular lens (IOL) was implanted in all 25 eyes. In 8 of 9 cases with rupture, the haptics were placed in the sulcus; in 1 case, the IOL was placed in the bag. One patient in the capsular rupture group developed macular edema 3 weeks postoperatively that responded to conservative treatment. Among 25 patients, 18 had a visual acuity of 20/20 to 20/30 and 6, 20/80 to 20/120. These 6 patients had residual posterior capsule plaque. All except 2 patients with plaque required a neodymium:YAG capsulotomy. In these patients, visual acuity improved to 20/30. In 1 patient, with microcornea, acuity did not improve to beyond 20/120. CONCLUSION: This study confirms the predisposition to posterior capsule rupture in eyes with posterior polar cataracts. Careful surgical planning produces satisfactory technical and visual outcomes.
PURPOSE: To assess the efficacy of newer surgical technique of sclerokeratoplasty in cases of refractory corneal ulcers of the cornea and to compare it with therapeutic penetrating keratoplasty. METHODS: A randomized, prospective clinical trial in 20 eyes with refractory corneal ulcers was undertaken. Ten eyes each underwent sclerokeratoplasty (group I) or therapeutic penetrating keratoplasty (group II). Infections were considered cured if there was no evidence of corneal infiltration for 1 month following keratoplasty. Postoperative complications, visual acuity (VA), keratometry and graft status were evaluated with both the procedures after a minimum follow up of 1 year. RESULTS: Postoperative complications included epithelial defects, shallow anterior chamber, uveitis and secondary glaucoma, which were present following both procedures, with no significant difference in the frequency of complications between the two techniques (P < 005), Graft clarity and VA with both procedures were comparable. Significantly reduced astigmatism of < 1 D was seen in six eyes in group II in comparison with group I, where astigmatism of > 1.5 D was present in six eyes. Two eyes in group II developed re-infection, of which one was re-operated on, and the other developed endophthalmitis. CONCLUSIONS: Sclerokeratoplasty is a useful alternative to therapeutic penetrating keratoplasty in cases of refractory corneal ulcers with optimum clinical and useful visual outcome.
BACKGROUND: Carotid body tumour is a rare neoplasm of the carotid body. Three cases of carotid body tumour presenting as a painless progressive mass in the neck region are reported here. A review of the relevant literature regarding carotid body tumours is also presented. METHODS: Angiographic features were diagnostic of carotid body tumour and complete surgical excision was done. RESULTS: There was no mortality and minimum morbidity. There were no malignant tumours. All three patients belong to the high-altitude area of Himachal Pradesh. CONCLUSIONS: A high degree of clinical suspicion of upper posterior triangle neck masses and an accurate diagnostic work-up are needed for operative planning.
An in vivo bromodeoxyuridine (BrdU) labeling index (LI) was estimated in 43 cases of astrocytic tumors and mixed gliomas by one hour intra-operative intravenous infusion at a dose of 200 mg/m2 and correlated with (a) histological grading using a computer aided malignancy classifier TESTAST-268; and (b) histological typing using WHO classification. The lowest BrdU LI was seen in pilocytic and gemistocytic astrocytomas followed by astrocytomas, anaplastic astrocytomas and glioblastoma multiforme in that order. Mixed oligoastrocytomas followed the pattern of their astrocytic counterparts. Tumors of similar histological type showed different BrdU LI values especially amongst astrocytomas and glioblastomas. A statistically significant difference in the BrdU LI was also noted between the higher TESTAST grades of astrocytomas (T III and IV) versus the lower TESTAST grades (T II). Unlike earlier reports in literature, in the present study the category of BrdU LI of <1 contained no case of anaplastic astrocytoma or glioblastoma multiforme (TESTAST grades III and IV). Likewise, the category of BrdU LI >5 contained only anaplastic astrocytoma and glioblastoma multiforme (TESTAST grades III and IV). Maximum spread of cases was seen in the BrdU LI category of 1-5, not only in terms of histological types but also TESTAST grades. Thus there appeared to be a positive trend of increasing BrdU LI values both with histological types and increasing TESTAST grades. Further, an interesting observation was that by using a combination of TESTAST grades and BrdU LI, the histologically homogenous glioblastoma group could be further subdivided into 4 categories which showed a trend towards prognostic correlation. Thus, this study though preliminary with number of cases being small in some groups, highlights the possible usefulness of combined histological typing, TESTAST grading and in vivo BrdU LI for prognostication of gliomas especially glioblastoma multiforme.
Five right-handed children with acquired aphasia elipepsy syndrome (Landau-Kleffner, LKS), were investigated with 99(m)TcHMPAO single photon emission computed tomography (SPECT) and the results were correlated with their EEGs and clinical history. The childrens' ages ranged from 2 to 5 years and the aphasia had been present for 6 to over 12 months. No clinical seizure had ever been onserved in the younger two children and their waking EEGs showed infrequent central spikes. Both children had areas of low intensity on SPECT, involving the left temporal lobe in one and the right temporal lobe in the other, which has also been reported in children with congenital dysphasia who have normal EEGs. The three older children presented with frequent generalized seizures, with the aphasia occurring 3-6 months later. The SPECT scans in these children were performed either in the ictal state, or when electrographic seizure activity was very frequent on EEG. All three children had hyperintense foci on SPECT involving the left posterior temporal region corresponding to Wernickes area. We conclude that LKS may be initially a unilateral seizure disorder of Wernickes area, with EEG discharges in the contralateral hemisphere representing propagation from the unilateral focus. Copyright 1999 Harcourt Publishers Ltd.
C3G is a guanine nucleotide-releasing protein that binds to the Src homology 3 (SH3) domain of the adapter protein Crk. In this study, we isolated cDNAs coding for rat C3G. Northern blot analysis of RNA from various rat tissues and cell lines showed a major transcript of about 7 kb which was present at the highest level in testis. A comparison of the amino acid sequence (derived from the cDNA sequence) of rat C3G with the human form showed 87.3% sequence identity. The principal difference was the presence of an additional 51 amino acids in the rat C3G sequence after the fifth PXXP motif. This difference may be attributable to alternative splicing of the primary transcript. This interpretation was supported by reverse transcription-polymerase chain reaction (RT-PCR) assays, which resulted in two products differing by 153 bp. The RT-PCR analysis of RNA from various rat tissues showed that the relative expression levels of the two splice forms were variable. The form of C3G with the insertion of 51 amino acids (named C3G-2) was present in rat testis at a high level and, to a lesser extent, in brain, but it was not seen (or was present at a very low level) in other rat tissues and certain rat and mouse cell lines. This expression pattern of the C3G-2 form was confirmed by Northern blotting using the insert region as a probe. The C3G-1 form, without the insertion of 51 amino acids, was present in almost all rat tissues except testis and in cell lines of rat, mouse, or human origin. Thus, in rat cells, we have identified a novel splice variant of C3G. The expression pattern indicates that the form of C3G described here is likely to serve a tissue- or cell-specific physiological function.
Twenty-six persons from five families comprising 34 members residing in different areas of Saptari district of the eastern region of Nepal developed symptoms of epidemic dropsy over 6-8 weeks. Seventeen patients were studied during July-August 1996. The age of affected individuals varied from 3 to 75 years. Members who had not consumed food cooked in mustard oil or who were not residing with the family were spared. Mustard oil, which was used for cooking, was found to be contaminated with oil of Argemone mexicana seeds. Sanguinarine was detected in all mustard oil samples collected from the homes of affected families. Gastrointestinal symptoms were present in 82 per cent of cases a week or so prior to the onset of pedal oedema. Pitting oedema of the lower limbs, fever, and darkening of the skin were the most consistent features, found in all cases. Other prominent features such as local erythema (82 per cent) and tenderness (88 per cent) of the lower limbs were present in most cases. Two striking features not previously noted were perianal itching (100 per cent) and severe carditis (35 per cent) with congestive cardiac failure (29 per cent). Other unique features noted were 'sarcoid' skin changes (18 per cent), bilateral pleural effusion, and Roth's spots and subhyloid haemorrhages in the fundus in one patient. Other important findings were anaemia (88 per cent), hepatomegaly (41 per cent), pneumonia (35 per cent) and ascites (12 per cent). There were no deaths due to epidemic dropsy. In the majority of cases, oedema, cutaneous changes, and carditis showed a marked improvement in 2-3 weeks and patients were well after 6-8 weeks of follow-up.
Reports are scanty regarding kala-azar in children in Nepal. In this communication we document 20 children diagnosed to have kala-azar who were admitted and treated at B. P. Koirala Institute of Health Sciences, Dharan, Nepal. The children were between 2 and 14 years old. The duration of illness varied between 12 days and 24 months with a majority (65 per cent) of children being ill for less than 6 months. Hepatomegaly and splenomegaly were seen in 95 and 90 per cent of cases respectively. Splenomegaly was not found in two (10 per cent) children. Anaemia, leucopenia, and thrombocytopenia were seen in 95, 60, and 75 per cent of children respectively. Amastigotes of Leishmania donovani (LD bodies) were demonstrated in Giemsa-stained smears of bone marrow aspirates in 16 (80 per cent) children. All the children responded to treatment with sodium stibogluconate. No mortality was observed. This study emphasizes the importance of kala-azar in children in endemic areas of eastern Nepal.
High-grade prostatic intraepithelial neoplasia (PIN) is the most likely precursor of prostate cancer. The effect of radiation therapy (RT) on the prevalence of PIN is uncertain. We studied 86 patients who underwent salvage radical prostatectomy after irradiation failure at the Mayo Clinic. The prevalence, volume, multicentricity, spatial proximity to cancer, and architectural patterns of PIN were evaluated. High-grade PIN was identified in 53 (62%) of 86 prostatectomy specimens. Multiple architectural patterns were usually observed, including tufting in 87%, micropapillary in 66%, cribriform in 38%, and flat in 17%. The mean volume of PIN was 0.12 cm3 (range, 0.05-1.20 cm3). PIN was usually multicentric (70%), with a mean number of PIN foci of 2.5 (range, 1-10). Ninety-four percent of PIN foci were located within 2 mm of invasive cancer. There was no correlation between PIN and pathologic stage, surgical margin, tumor size, DNA ploidy, post-RT Gleason score, time interval from RT to biopsy-proven recurrence, postoperative prostate-specific antigen level, distant metastasis-free survival, or cancer-specific survival. Our examination of salvage radical prostatectomy specimens indicated that the prevalence and extent of PIN appeared to be reduced after RT compared to published studies of prostatectomies without prior RT.