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Biomedical subjects

J Singh

Publications and source records attributed to J Singh.

At least 199 records · Page 11Linked to original sources
PubMed1999

Of bugs and drugs. A guide through the labyrinth of antimicrobial therapy for respiratory tract infections.

Choosing appropriate antimicrobial therapy is no longer a simple process. Even for the common problems of respiratory tract disease in children and adults, selection is complicated by both increasing microbial resistance and the daunting number of extended-spectrum antibiotics now on the market. In this article, Drs Singh and Arrieta look at the problem from all aspects and give their specific recommendations.

Acute Disease↗
PubMed1999

Inhibition by dietary menhaden oil of cyclooxygenase-1 and -2 in N-nitrosomethylurea-induced rat mammary tumors.

Studies in laboratory animals and epidemiological surveys suggest a relationship between the type and amount of dietary fat and mammary cancer. One mechanism proposed to explain this relationship is modulation by dietary fat, of mammary tumor eicosanoid levels through action at the rate limiting enzyme in eicosanoid synthesis, cyclooxygenase (COX). Until recently there have been no studies which have examined COX gene expression in human breast or rodent mammary tissues. In this study we have demonstrated the presence of two immunoreactive isoforms of cyclooxygenase (COX-1 and -2), and the modulating effects of n-3 fatty acids on their expression, in N-nitrosomethylurea (NMU)-induced rat mammary tumors. Three different high fat diets were compared namely, corn oil (CO) 23%; CO 18% menhaden oil (MO) 5%; CO, 5%/MO 18%; low fat corn oil (5%) served as a control. It was found that immunoreactive COX-2 protein levels were approximately 3x higher than COX-1 levels in NMU-induced mammary tumors. Moreover, the high menhaden oil diet (rich in n-3 fatty acids) significantly suppressed both COX-1 (-28%) and COX-2 (-36%) protein levels when compared to the high corn oil diet. No differences were found among the other treatment groups when compared pair-wise or with low-fat control. The mechanism(s) by which n-3 fatty acids suppress COX-1 and COX-2 remain to be determined.

Animals↗
PubMed1999

Indinavir-induced nephropathy.

We report the case of a 38-year-old male who developed renal insufficiency while on the protease inhibitor, indinavir. This patient had an increase in serum creatinine over a period of approximately one year, along with persistently abnormal urinalysis. A renal biopsy was performed and showed marked tubular crystal deposition. The indinavir was discontinued, and after two months the patient's serum creatinine and urinalysis returned to normal. To our knowledge this is the second case of indinavir associated nephropathy.

Adult↗
PubMed1999

Role of neurotrophin-trk interactions in oncology: the anti-tumor efficacy of potent and selective trk tyrosine kinase inhibitors in pre-clinical tumor models.

The increasing knowledge of the pathogenic mechanisms involved in cancer cell growth has enabled the implementation of mechanism based drug design approaches rather than the more conventional nonspecific approaches. Drugs that interfere with cellular signal transduction pathways are currently a major focus in development of newer therapeutic technologies in oncology. The therapeutic utility of potent and selective tyrosine kinase inhibitors in oncologic applications has become widely recognized for several years, however targeting neurotrophin receptors as a molecular target driven approach has only recently been realized. This review presents the hypothesis of the neurotrophin-trk receptors as a viable molecular target for medicinal chemical intervention in tumor biology, followed by an overview of the pre-clinical studies which culminated in the advancement of the first potent trk tyrosine kinase inhibitor CEP-2563 (KT-8391), and the orally active K-252a analog, CEP-701 (KT-5555) into clinical evaluation.

Animals↗
PubMed1999

Widespread outbreaks of measles in rural Uttar Pradesh, India, 1996: high risk areas and groups.

OBJECTIVE: To describe outbreaks of measles which affected many districts in Uttar Pradesh (UP) during 1996. DESIGN: Outbreak investigations. SETTING: The state of Uttar Pradesh, India. METHODS: The reported data on measles morbidity, mortality and vaccine coverage from 1991 through 1996 were reviewed. Reported vaccine coverage levels were compared with the results of coverage surveys carried out in UP from 1992 through 1996. Line lists on measles cases were analyzed to ascertain the age, immunization status, geographical distribution, and age and sex-specific fatality ratios during the outbreaks. A community survey was organized in 7 affected villages to estimate vaccine effectiveness. RESULTS: Fifty one of 68 districts in UP reported 6922 measles cases and 281 deaths in 1996. The majority of cases and deaths occurred in June and July which are usually low transmission months. Overall cases fatality ratio (CFR) was 4.1%. CFRs were significantly higher in females and young children. The median age of cases was found to be below 5 years. There was heavy clustering of cases and deaths in rural areas. About 85% of the cases and virtually all the measles associated deaths occurred in unvaccinated children. Published documents on statewide coverage surveys revealed that the measles vaccine coverage levels ranged between 26% and 36% during 1992-96. Large gaps were found between reported coverage and survey results. Nevertheless, epidemiological studies indicated a vaccine effectiveness of more than 90%. CONCLUSIONS: The outbreaks occurred due to poor vaccine coverage levels and an inefficient surveillance system which failed to generate early warning signals. The study highlights the urgent need to raise the vaccine coverage levels rapidly in all districts to achieve measles control and prevent future outbreaks in UP.

Age Distribution↗
PubMed1999

Epidemiological characteristics of poliomyelitis in Delhi, 1997.

OBJECTIVE: To describe the epidemiological characteristics of poliomyelitis in Delhi in 1997 after four consecutive statewide immunization campaigns with oral polio vaccine (OPV). METHODS: Stool samples were collected from 158 cases of acute flaccid paralysis (AFP) along with their age, sex, residential address, immunization history and dates of onset of paralysis, reporting and investigation. The samples were processed for isolation of polioviruses. In addition, historical data on vaccination coverage surveys and OPV testing were reviewed. These data were analyzed to understand the epidemiological patterns of poliomyelitis in Delhi. RESULTS: Of 158 cases of AFP, about 23% were investigated within 2 days of onset of paralysis. Two samples each were collected from 97 (61%) cases, and one each from the remaining cases. Detection of 158 cases of AFP gave an incidence of 1.34 per 100,000 population. About 36% (57/158) of AFP cases excreted poliovirus, mostly (53/158) wild poliovirus. Of the wild poliovirus isolates, 72% (38/53) and 25% (13/53) were serotypes P1 and P3 respectively; 2 isolates were P2. Almost 95% (146/154) of AFP cases and all the laboratory confirmed cases (excreting wild poliovirus) occurred in children below 5 years of age. Only one-third of AFP (55/158) or laboratory confirmed cases (18/53) had received 3 or more doses of OPV before onset of paralysis. About one-fourth of cases in both the categories were totally unvaccinated. AFP cases occurred round the year but peaked in November-December. Peaks were always observed during July-August in the past. The cases were widely scattered without any obvious clustering in any locality. CONCLUSIONS: Poliomyelitis has declined substantially in Delhi. The study underscores the need for further efforts to improve vaccine coverage levels, AFP surveillance, and cold chain maintenance to achieve the complete interruption of transmission.

Child↗
PubMed1998

Mechanisms of percutaneous absorption of tamoxifen by terpenes: eugenol, D-limonene and menthone.

The effect of chemical penetration enhancers (e.g., eugenol, d-limonene and menthone in combination with 50% ethanol) on the in vitro percutaneous absorption of tamoxifen through porcine epidermis has been investigated. The above enhancers significantly increased (p<0.05) the permeability coefficient of tamoxifen in comparison with the control (50% ethanol). Fourier transform infrared spectroscopy (FT-IR) was employed to investigate the biophysical changes in the stratum corneum (SC) lipids by the enhancer(s). FT-IR results showed that the treatment of the SC with enhancers did not produce a blue shift in the asymmetric and symmetric C-H stretching peak positions. However, all of the above enhancers showed a decrease in peak heights and areas for both asymmetric and symmetric C-H stretching absorbances in comparison with the untreated SC. A decrease in peak heights and areas is a measure of lipid extraction. Partitioning of tamoxifen to powdered SC from control and enhancer solutions was also determined. FT-IR and partitioning studies reveal that the enhancement in the permeability coefficient of tamoxifen by eugenol and d-limonene is due to lipid extraction and improvement in the partitioning of the drug to the SC. However, menthone enhanced the permeability of tamoxifen by increasing extraction of the SC lipids and not by improving the partitioning of the drug to the SC.

Animals↗
PubMed1998

Chromium(III) decreases the fidelity of human DNA polymerase beta.

Certain particulate compounds of hexavalent chromium are well-known occupational and environmental human carcinogens. Hexavalent chromium primarily enters the cells and undergoes metabolic reduction; however, the ultimate trivalent oxidation state of chromium, Cr(III), predominates within the cell. DNA-bound Cr(III) has been previously shown to decrease the fidelity of replication in the M13 phage mutation assay. This study was done to understand how Cr(III), in the presence of physiological concentrations of magnesium, affects the kinetic parameters of steady-state DNA synthesis in vitro across site-specific O6-methylguanine (m6dG) residues by DNA polymerase beta (pol beta). Cr(III) binds to the short oligomer templates in a dose-dependent manner and stimulates the activity of pol beta. Cr(III) stimulates the mutagenic incorporation of dTTP opposite m6dG more than the nonmutagenic incorporation of dCTP, and thereby Cr(III) further decreases the fidelity of DNA synthesis across m6dG by pol beta. In contrast, Cr(III) does not affect the fidelity of DNA synthesis across the normal template base, dG. Both the enhanced activity and the mutagenic lesion bypass in the presence of Cr(III) may be associated with Cr(III)-dependent stimulation of pol beta binding to DNA as reported here. This study shows some of the mechanisms by which mutagenic chromium affects DNA synthesis.

Binding Sites↗
PubMed1998

Age-related changes in morphology and secretory responses of male rat lacrimal gland.

This study investigates the differences in the outward appearance and morphology of lacrimal glands, the morphology within the lacrimal acinar cells and the secretion of protein from acinar cells of young (3-5 months) and aged (20 and 24 months) male rats. The appearance of the glands, as seen by the naked eye, differed between the three age-groups. The lacrimal gland of young animals was a smooth pink tissue, while the tissue from aged animals appeared lobular and white in colour, thought to result from infiltration of fatty/connective tissue. Glands from 24 month old animals had a more pronounced lobular appearance than the glands from 20 month old animals. Light microscopy studies revealed that as the animals aged there was evidence of progressive morphological changes. These changes included thickening of the connective tissue sheath, chronic inflammation with increased infiltration by mast cells, patchy destruction of ductal and vascular tissues, enlargement of lacrimal ducts, luminal swelling of the acini, and changes in acinar type. Electron microscopy (EM) studies revealed the presence of 3 types of acini in the rat lacrimal gland: acini which contained only protein secretory granules (serous acini), acini which contained protein and mucous secretory granules (seromucous acini), and acini which contained only mucous secretory granules (mucous acini). In young glands the majority of acini were serous with a few seromucous acini and even fewer mucous acini. In aged glands there were significant reductions in serous acini (ANOVA; P < 0.01) when compared to the young glands. In 20-month-old glands, there were marked increases in the percentage occurrence of seromucous acini, while in 24 month old glands, there were large increases in the relative number of mucous acini. Qualitative EM studies demonstrated that the typical acini from young glands contained numerous protein secretory granules. Ageing was associated with a progressive loss of protein (serous) secretory granules. Furthermore, marked changes and patchy destruction of the endoplasmic reticulum and Golgi apparatus were observed in acini of glands from aged rats when compared to acini of glands from young rats. Measurement of total protein output from acini revealed a significant (Student's t-test, P < 0.05) decrease in protein secretion from aged glands compared to glands from young animals. These results suggest that not only is there considerable structural damage, chronic inflammation and mast cell infiltration to the lacrimal gland with ageing, but also possible redifferentiation of acini from serous to seromucous and then to mucous acini. Furthermore, the results also suggest a reduction or an inability of the acini to synthesise and to secrete protein from glands of aged animals compared to glands of young rats. All of these changes appear to occur more rapidly as the rats mature between 20 and 24 months. These findings provide a morphological basis to explain the phenomenon of reduced tear/protein secretion with ageing.

Acetylcholine↗
PubMed1998

In vitro percutaneous absorption enhancement of a lipophilic drug tamoxifen by terpenes.

Tamoxifen is a highly lipophilic drug that is widely used in breast malignancies and also as a prophylactic therapy in women at high risk for the development of this disease. Recently, the terpenes have been reported to show an enhancement effect on percutaneous drug absorption. The effect of terpenes (e.g. carvone, 1,8-cineole, menthol, and thymol) was studied on the in vitro percutaneous absorption of tamoxifen through porcine epidermis. The above terpenes (5% w/v) in combination with 50% ethanol significantly (P < 0.01) increased the permeability coefficient of tamoxifen in comparison to the control (50% ethanol). The solubility of tamoxifen was determined in the control and enhancer solutions to correct the permeability enhancement by way of fractional solubility adjustment. Binding of tamoxifen to powdered stratum corneum from control and enhancer solutions was also determined. Binding studies reveal that the enhancement in the permeability coefficient of tamoxifen by menthol and thymol is due at least in part, to improvement in the partitioning of the drug to the stratum corneum. In conclusion, terpenes in combination with ethanol can be used to enhance the percutaneous absorption of the highly lipophilic drug tamoxifen.

Animals↗
PubMed1998

Ribosomes mask cytochrome b5 on rough microsomal vesicles.

Cytochrome b5 is unmasked on the removal of ribosomes by chemical degranulation of rat liver microsomes. Reattachment of ribosomes to stripped membranes remasks this enzyme on the membrane surface. This haemoprotein may be involved either in the attachment of ribosomes to reticular membranes or in protein biosynthesis by membrane-bound ribosomes.

Animals↗
PubMed1998

The role of polar interactions in the molecular recognition of CD40L with its receptor CD40.

CD40 Ligand (CD40L) is transiently expressed on the surface of T-cells and binds to CD40, which is expressed on the surface of B-cells. This binding event leads to the differentiation, proliferation, and isotype switching of the B-cells. The physiological importance of CD40L has been demonstrated by the fact that expression of defective CD40L protein causes an immunodeficiency state characterized by high IgM and low IgG serum levels, indicating faulty T-cell dependent B-cell activation. To understand the structural basis for CD40L/CD40 association, we have used a combination of molecular modeling, mutagenesis, and X-ray crystallography. The structure of the extracellular region of CD40L was determined by protein crystallography, while the CD40 receptor was built using homology modeling based upon a novel alignment of the TNF receptor superfamily, and using the X-ray structure of the TNF receptor as a template. The model shows that the interface of the complex is composed of charged residues, with CD40L presenting basic side chains (K143, R203, R207), and CD40 presenting acidic side chains (D84, E114, E117). These residues were studied experimentally through site-directed mutagenesis, and also theoretically using electrostatic calculations with the program Delphi. The mutagenesis data explored the role of the charged residues in both CD40L and CD40 by switching to Ala (K143A, R203A, R207A of CD40L, and E74A, D84A, E114A, E117A of CD40), charge reversal (K143E, R203E, R207E of CD40L, and D84R, E114R, E117R of CD40), mutation to a polar residue (K143N, R207N, R207Q of CD40L, and D84N, E117N of CD40), and for the basic side chains in CD40L, isosteric substitution to a hydrophobic side chain (R203M, R207M). All the charge-reversal mutants and the majority of the Met and Ala substitutions led to loss of binding, suggesting that charged interactions stabilize the complex. This was supported by the Delphi calculations which confirmed that the CD40/CD40L residue pairs E74-R203, D84-R207, and E117-R207 had a net stabilizing effect on the complex. However, the substitution of hydrophilic side chains at several of the positions was tolerated, which suggests that although charged interactions stabilize the complex, charge per se is not crucial at all positions. Finally, we compared the electrostatic surface of TNF/TNFR with CD40L/CD40 and have identified a set of polar interactions surrounded by a wall of hydrophobic residues that appear to be similar but inverted between the two complexes.

Amino Acid Sequence↗
PubMed1998

Identification of a Frizzled-like cysteine rich domain in the extracellular region of developmental receptor tyrosine kinases.

In Drosophila, members of the Frizzled family of tissue-polarity genes encode proteins that appear to function as cell-surface receptors for Wnts. The Frizzled genes belong to the seven transmembrane class of receptors (7TMR) and have on their extracellular region a cysteine-rich domain that has been implicated as the Wnt binding domain. This region has a characteristic spacing of ten cysteines, which has also been identified in FrzB (a secreted antagonist of Wnt signaling) and Smoothened (another 7TMR, which is involved in suppression of the hedgehog pathway). We have identified, using BLAST, sequence similarity between the cysteine-rich domain of Frizzled and several receptor tyrosine kinases, which have roles in development. These include the muscle-specific receptor tyrosine kinase (MuSK), the neuronal specific kinase (NSK2), and ROR1 and ROR2. At present, the ligands for these developmental tyrosine kinases are unknown. Our results suggest that Wnt-like ligands may bind to these developmental tyrosine kinases.

Amino Acid Sequence↗
PubMed1998

Differential sensitivity of chromium-mediated DNA interstrand crosslinks and DNA-protein crosslinks to disruption by alkali and EDTA.

Some compounds of hexavalent chromium are well-established carcinogens. Chromium enters mammalian cells in the hexavalent form and is reduced to chromium (III). Treatment of purified DNA with chromium (III) produces DNA-DNA interstrand crosslinks (DDC) which obstruct the progression of DNA polymerases in vitro. DDC were also detected in chromate-treated cultured normal human lung cells using the renaturing agarose gel electrophoresis (RAGE) assay and correlated with base-specific inhibition of DNA replication. Curiously, DDC have gone undetected in studies of cultured cells using the alkaline elution (AE) technique, whereas chromium-mediated DNA-protein crosslinks (DPC) were readily detected by AE. We tested the hypothesis that AE conditions [60 mM tetraethyl ammonium hydroxide (TEA), 20 mM EDTA, pH 12.6, for 16 h at room temperature] dissociate DDC but not DPC using chromium(III)-treated plasmid DNA and the RAGE assay. Dose-dependent chromium-induced DDC were unaffected by TEA (pH 11.8) alone or by more rigorous alkaline denaturation conditions (200 mM NaOH, pH 13.5, for 16 h). DDC were, however, completely disrupted by EDTA (pH 12.6) alone or the combination of TEA and EDTA (pH 12.6). In contrast, DPC remained largely intact under these conditions. Therefore, past AE-based studies which have failed to detect chromium-induced DDC do not prove the absence of this lesion. AE may not be suitable for detecting DDC induced by EDTA-chelatable agents such as metals.

Caustics↗