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Biomedical subjects

G Singh

Publications and source records attributed to G Singh.

At least 415 records · Page 23Linked to original sources
PubMed1993

Human Clara cell 10-kDa protein is the counterpart of rabbit uteroglobin.

Human Clara cell 10-kDa protein has been suggested to be a counterpart of rabbit uteroglobin, an immunomodulatory and antiinflammatory secretory protein. Since this human protein is not readily available in substantial quantity for detailed characterization of its biochemical, biological, and pharmacological properties, we sought to express it in Escherichia coli in order to study its structure-function relationship. However, bacterial overproduction of homodimeric proteins with interchain disulfide bonds, such as Clara cell 10-kDa protein, was thought to be impossible until we achieved expression of native uteroglobin (Miele, L., Cordella-Miele, E., and Mukherjee, A.B. (1990) J. Biol. Chem. 265, 6427-6435). Here, we report high level production of recombinant native dimeric human Clara cell 10-kDa protein in E. coli and its characterization. Recombinant human Clara cell 10-kDa protein forms its disulfide bonds within the bacterial cytoplasm. The purified protein possesses two of the most important activities characteristic of uteroglobin: (i) it is an excellent substrate of transglutaminase, and (ii) it is a potent inhibitor of porcine pancreatic and, more importantly, human synovial phospholipase A2. These results demonstrate that human Clara cell 10-kDa protein and rabbit uteroglobin have very similar biochemical properties. Our data suggest that this protein may possess immunomodulatory and antiinflammatory activities of potential physiological and pharmacological importance.

Amino Acid Sequence↗
PubMed1993

Autoradiographic analyses of guinea pig airway tissues following inhalation exposure to 14C-labeled methyl isocyanate.

Through the use of radioactively labeled methyl isocyanate (MIC), the deposition, penetration, and clearance of this highly reactive compound in the airway at the tissue and cellular levels have been directly examined. Guinea pigs were exposed to 14C-MIC vapors at concentrations ranging from 0.38 to 15.2 ppm for periods of 1-6 hr. Solubilization of tissues from these animals showed the airway tissues to have the highest level of radioactivity. In the nasal region, 14C deposition, as monitored by histoautoradiography, was limited to the epithelial layer, was related to dose, and was dependent on the specific epithelial cell type. The squamous epithelium was minimally labeled on the surface and the label did not penetrate the cell layer. However, radioactivity was detected throughout the entire nasal respiratory epithelial layer. The lack of nasal deposition in tracheotomized animals demonstrated that the 14C accumulation at this site was due to the scrubbing action of the nasal region with no contribution from blood recirculation. Cellular localization in the tracheobronchial region showed epithelial and subepithelial deposition in a dose-dependent manner with accumulation of the label at the subepithelial region. Radioactivity penetrated to the level of the terminal bronchiole but was not detected in the alveolar region. The persistence of airway radioactivity over the 48-hr postexposure period monitored suggests the covalent modification of airway macromolecules. Despite its broad specificity and high reactivity, MIC undergoes selective reactions in the airways which are dependent on respiratory region and cell type.

Administration, Inhalation↗
PubMed1993

The prevalence of congenital orthopaedic anomalies in a rural community.

A rural Indian population of 50,055 was studied for the detection of congenital orthopaedic anomalies by a door-to-door survey. An incidence of 2.25 cases per 1000 population was found. Club foot was the commonest anomaly at 0.9 per 1000, followed by polydactyly and syndactyly at 0.45 and 0.38 cases per 1000. The most common anomaly found in females was a congenital short 4th metatarsal (0.24 per 1000).

Bone and Bones↗
PubMed1993

Mechanisms involved in the metastasis of cancer to bone.

The metastasis of cancer to bone is a frequent outcome of common malignancies and is often associated with significant morbidity due to osteolysis. Bone metastasis is also selective in that a disproportionately small number of malignancies account for the majority of tumors which spread to bone. While the mechanisms of bone destruction have been studied, those responsible for the site-specific nature of bone metastasis are poorly understood. As a metastatic target, bone is unique in that it is continuously being remodelled under the influence of local and systemic growth factors, many of which are embedded in the bone matrix. This review summarizes evidence for the hypothesis that the formation of metastatic tumors in bone is the consequence of a unique microenvironment where metastatic cells can alter the metabolism of bone, thereby regulating the release of soluble bone-derived growth factors as a consequence of bone resorption. These, in turn, can modulate the malignant phenotypic properties of receptive cells. Transforming growth factor-beta is one factor which can promote the growth and motility of Walker 256 cells, a rat cell line with a propensity to metastasize spontaneously to bone.

Animals↗
PubMed1993

Tauromustine is more effective than conventional chemotherapy in the treatment of colonic tumors.

Despite recent advances in chemotherapy, the prognosis of advanced colorectal cancer remains poor. Although the taurine-based nitrosourea tauromustine (TCNU) has demonstrated schedule-dependent synergism with 5-fluorouracil (5-FU) and leucovorin (LV) against a variety of tumors in vitro, its efficacy relative to and in combination with these drugs in vivo remains unknown. To study this, BALB/C mice had C26 tumor implanted subcutaneously five days prior to the following treatment (doses and route of administration being the same in all groups): Group 1--no treatment; Group 2--TCNU (30 mg/kg by gavage); Group 3--LV (100 mg/kg intraperitoneally [IP]) and, one hour later, LV plus 5-FU (100 mg/kg IP); Group 4--LV and, one hour later, LV plus 5-FU and TCNU; and Group 5--TCNU and, on the following day, LV and, one hour later, LV plus 5-FU. All treatments were repeated seven days later. Body weight and tumor weight were measured twice weekly, and survival was noted. Postmortems were performed in all animals, and evidence of primary or secondary tumor was recorded. All surviving animals were sacrificed at 60 days. We found that 1) 87 percent of animals receiving TCNU and 60 percent of animals receiving LV, 5-FU, and TCNU survived to day 60; none of these animals had evidence of tumor when sacrificed; 2) animals in all other groups died by day 34; 3) evidence of metastases was found in five animals in Group 1 and one each in Groups 2 and 5; and 4) administering TCNU 24 hours prior to 5-FU plus LV resulted in death from toxicity in all animals. Thus, while synergism between TCNU and 5-FU plus LV was not seen, the antitumor properties of TCNU are significantly greater than those of conventional chemotherapy.

Animals↗
PubMed1993

Phase I clinical trial of an injectable contraceptive for the male.

Earlier studies on the rat and the monkey had demonstrated that an injection of styrene maleic anhydride (SMA) in a solvent vehicle of dimethyl sulphoxide (DMSO) into the lumen of the vas deferens is toxicologically safe and has contraceptive action. Phase I clinical trial was therefore undertaken on 38 male volunteers giving varying doses of SMA, ranging between 5 mg and 140 mg, into each vas deferens. A dose of 70 mg is the predicted therapeutic dose based on animal data. That the compound is within the vas deferens lumen during the period of the safety assessment is inferred from the effect on the spermatozoa count in ejaculates which reach azoospermic levels in the higher dose ranges. The treatment is well tolerated with only minimal side effects in a few cases and no long-term adverse effects.

Adult↗
PubMed1993

Time trends, cohort effects, and geographic patterns in stroke mortality--United States.

Trends and patterns in cerebrovascular disease mortality from 1940 to 1991 are examined using provisional and final mortality data from the US National Vital Statistics System. Trends are analyzed in terms of both period and cohort effects. Monthly data are examined using a time series regression model. Geographic patterns use maps ranking state mortality relative to the US average. Final 1989 data indicate that cerebrovascular disease remains the third leading cause of death in the United States, accounting for 145,551 deaths, or 6.8% of deaths from all causes. The age-adjusted death rate from stroke declined one-third during 1979 to 1989, more rapidly than the other ten leading causes of death. Overall, stroke mortality declined steadily from 1950 through the mid-1970s, then accelerated. On a cohort basis, each successive birth cohort since 1890 has improved their life-span experience from stroke deaths. Maps of stroke mortality demonstrate a persistent "stroke belt" in the South over the past decade.

Adult↗
PubMed1993

Restoration of gut absorptive capacity following trauma-hemorrhagic shock by the adjuvant use of heparan sulfate.

The aim of this study was to investigate whether heparan sulfate, as an adjunct to resuscitation following hemorrhagic shock: (1) improves gut absorptive capacity and if so, (2) whether the mechanism involved is alteration of whole blood viscosity (WBV). Rats were anesthetized, a laparotomy performed, and blood vessels cannulated. The conscious animals then underwent fixed pressure (40 mm Hg) hemorrhage, followed by resuscitation with lactated Ringer's solution. One group received 7 mg/kg heparan sulfate, and another received saline, during resuscitation. At 2 hours and 4 hours after the end of hemorrhage, the oral D-xylose absorption test was performed. Viscosity determinations were made in another set of rats since lactated Ringer's solution replacement during the D-xylose test may affect hematocrit and hence WBV. These rats were subjected to hemorrhage and resuscitation as above, along with additional sham hemorrhage and acute hemodilution control groups. The WBV was determined at corresponding times to the D-xylose test. Results show that xylose absorption is depressed after hemorrhage and resuscitation, and heparan sulfate restored it to normal. The WBV was reduced by heparan sulfate. Thus heparan sulfate, as an adjunct to resuscitation of hemorrhagic shock, restores gut absorptive capacity to normal, possibly by reducing WBV.

Animals↗
PubMed1993

Bile duct cysts: presentation in adults.

Bile duct or choledochal cysts are rare congenital anomalies and presentation in adult is infrequent. Seven cases of type I/IV bile duct cysts presenting in adult life have been treated by the authors during the past 2 years. The diagnosis was made using a combination of ultrasound and cholangiography (endoscopic retrograde cholangiopancreatography/percutaneous transhepatic cholangiography). All cases underwent total cyst excision and Roux-en-Y hepaticojejunostomy. There were no operative complications and all patients were asymptomatic in the follow-up period, which ranged from 3 to 23 months.

Adolescent↗
PubMed1993

An extraintestinal, pathogenic isolate of Escherichia coli (O4/K54/H5) can produce a group 1 capsule which is divergently regulated from its constitutively produced group 2, K54 capsular polysaccharide.

We are studying an O4/K54/H5 Escherichia coli bacteremic isolate (CP9) as a model pathogen for extraintestinal infection. Its group 2, K54 capsular polysaccharide is an important virulence determinant and confers serum resistance. In this study the effect of the group 1 capsule regulators, RcsA, RcsB, and Lon protease, on the regulation of CP9's capsular polysaccharides was assessed. It was established that in the presence of multicopy rcsA or with disruption of lon, CP9 can be induced to produce a group 1 capsule. RcsA, RcsB, and Lon are present in this K54 background and regulate group 1 capsule expression in a fashion similar to that described for K-12 strains. Two independent group 2 capsule gene protein fusions (cl1.29::TnphoA and cl1.137::TnphoA) were used to evaluate the effects of these regulators on group 2 K54 capsule production. Disruption of lon resulted in 1.9-fold (TR293 [cl1.29::TnphoA lon-146]) and 3.4-fold (TR1373 [cl1.137::TnphoA lon-146]) decreases in fusion activity at 28 degrees C, relative to the baseline level. However, decreases in fusion activity at 42 degrees C were only 1.2- and 1.4-fold, respectively. Inactivation of both lon and rcsA or lon and rcsB restored fusion activity to baseline levels at 28 degrees C, but only a partial restoration of activity was seen at higher temperatures. To assess whether these differences in fusion activity reflected a functional change in capsule production, the effects of 80% normal human serum (NHS) were tested against CP9 and TR93 (lon-146). Since the group 2 K54 capsule protects against the bactericidal activity of 80% NHS, a decrease in its production results in an increase in serum sensitivity. Viable counts of CP9 increased 10-fold in 80% NHS over 3 h at 28 degrees C, as expected. In contrast to CP9, TR93 (lon-146) incurred a 10-fold loss in viability under the same conditions. The levels of RcsA are increased in TR93 (lon 146) as consequence of lon disruption; therefore, these results in conjunction with the cl1::TnphoA protein fusion data establish RcsA as a negative regulator of the group 2 K54 capsular polysaccharide. Furthermore, these results also suggest existence of another Lon-sensitive negative regulator of group 2 K54 capsule production, which is active higher temperatures.

ATP-Dependent Proteases↗
PubMed1993

Actions of Helodermatidae venom peptides and mammalian glucagon-like peptides on gastric chief cells.

The actions of peptides (helospectin I, helodermin, exendin-3, exendin-4) that have been isolated from the venoms of Helodermatidae lizards were examined using dispersed chief cells from guinea pig stomach. These actions were compared with those of mammalian glucagon-like peptides, particularly truncated glucagon-like peptide 1 (TGLP-1), a peptide that shares 53% homology with exendin-4. The Helodermatidae venom peptides and TGLP-1 caused a two- to threefold increase in chief cell adenosine 3',5'-cyclic monophosphate and pepsinogen secretion. Exendin-3 and exendin-4 were 100 times more potent than helospectin I and helodermin and 10 times more potent than TGLP-1. Helospectin I and helodermin, but not exendin-4 or TGLP-1, inhibited the binding of 125I-labeled vasoactive intestinal peptide (VIP) and 125I-secretin to dispersed chief cells. The actions of exendin-3, exendin-4, and TGLP-1, but not those of helospectin I, helodermin, VIP, or secretin, were progressively inhibited by increasing concentrations of an exendin-receptor antagonist, exendin-(9-39)-NH2. These data indicate that in gastric chief cells, whereas the actions of helospectin I and helodermin are mediated by interaction with high-affinity secretin (low-affinity VIP) receptors, the actions of exendin-3, exendin-4, and TGLP-1 are mediated by interaction with exendin receptors.

Amino Acid Sequence↗