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Biomedical subjects

V K Shukla

Publications and source records attributed to V K Shukla.

At least 73 records · Page 4Linked to original sources
PubMed1997

Chronic typhoid carriage and carcinoma of the gallbladder.

Chronic microbial infections and/or their carrier state have been reported to be associated with particular cancers. Since typhoid infections and carcinoma of the gallbladder (the site where salmonella usually persists) are endemic in northern India, it was considered important to explore the relationship between the two. In the present study, a total of 1001 bile specimens collected from cases of carcinoma of the gallbladder (28), cholelithiasis (56) and individuals without biliary pathology (17) were subjected to aerobic cultures that had been enriched for salmonella. Salmonella typhi and S. paratyphi-A could be detected in a significantly higher (P < 0.05) number in patients with carcinoma of the gallbladder as compared with cholelithiasis and control groups. The existence of such an association indicates that detection and eradication of typhoid carriers may lead to a decrease in the incidence of carcinoma of the gallbladder along with typhoid fever.

Bile↗
PubMed1997

Design of potent dynorphin A-(1-9) analogues devoid of supraspinal motor effects in mice.

Four analogues of dynorphin (Dyn) A-(1-9) incorporating D-Leu in position 8 alone or in combination with the nonhydrolysable psi [CS-NH] thiopeptide bond surrogate between positions 6 and 7 were tested in vitro for their ability to compete with the binding of selective kappa, mu, and delta opioid ligands, using membrane preparations of guinea pig cerebellum (kappa) and rat brain (mu and delta), for their ability to block the electrically induced contractions of the guinea pig ileum, and for their in vivo antinociceptive (writhing test) and motor (motor dysfunction assay) activities in mice. [D-Leu8]Dyn A-(1-9) displayed an affinity and a selectivity for the kappa opioid receptor that were comparable with those of Dyn A-(1-9). The potencies of [D-Leu8]Dyn A-(1-9) in the guinea pig ileum, writhing, and motor dysfunction assays were markedly enhanced (8-12 fold) compared with those of Dyn A-(1-9). [6 psi 7(CS-NH),D-Leu8]Dyn A-(1-9), [Lys6, 6 psi 7(CS-NH),D-Leu8] Dyn A-(1-9), and [Leu6, 6 psi 7(CS-NH), D-Leu8]Dyn A-(1-9) were somewhat less potent than [D-Leu8]Dyn A-(1-9) in all opioid assays. However, the thiopeptides were more potent analgesics than Dyn A-(1-9)(ED50 of 29.5, 23.9, and 15.5 nmol/mouse, respectively, compared with 90.7 nmol/mouse for Dyn A-(1-9)) and caused little or no motor impairment at analgesic doses.

2-Amino-5-phosphonovalerate↗
PubMed1997

N-methyl-D-aspartate antagonist activity of alpha- and beta-sulfallorphans.

Resolved equatorial (alpha) and axial (beta) forms of S-allylmorphinans, alpha-sulfallorphan and beta-sulfallorphan, were tested for their ability to compete with the binding of phencyclidine and sigma receptor ligands to mouse brain membranes and to antagonize N-methyl-D-aspartate (NMDA)-induced convulsions in mice. alpha- and beta-sulfallorphans displayed distinct binding affinities for phencyclidine and sigma sites, inhibiting the binding of [3H]-(5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten++ +-5, 10-imine ([3H]MK-801) with Ki values of 2.32 and 0.13 microM and that of [3H](+)-pentazocine with Ki values of 1.97 and 1.61 microM, respectively. Intracerebroventricular administration of these compounds in mice caused dose-dependent inhibitions of NMDA-induced convulsions, but did not affect convulsions induced by (R,S)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA), kainic acid and bicuculline. alpha- and beta-sulfallorphans blocked the convulsive activity of NMDA (1 nmol/mouse; intracerebroventricular) with ED50 values of 0.48 and 0.015 nmol/mouse, as compared with 0.55, 0.039 and 0.013 nmol/mouse for dextrorphan, MK-801 and (+/-)3-(2-carboxypiperazine-4yl)propyl-1-proprionic acid, respectively. The structurally related compound, dextrallorphan, significantly but less potently blocked NMDA-induced convulsions (ED60, 2.68 nmol/mouse). At the protective doses, alpha- and beta-sulfallorphans markedly reduced NMDA- and AMPA-induced mortality without inducing locomotion and falling behavior. These results indicate that alpha- and beta-sulfallorphans are potent and selective NMDA antagonists devoid of motor side effects at protective doses.

Animals↗
PubMed1997

Nonopioid motor effects of dynorphin A and related peptides: structure dependence and role of the N-methyl-D-aspartate receptor.

Dynorphin (Dyn) A and related opioid and nonopioid peptides were tested for their ability to produce motor effects in mice. Central (intracerebroventricular) administration of Dyn A in mice produced marked motor effects characterized by wild running, jumping, circling and/or barrel rolling with an ED50 value of 14.32 (95% confidence limits, 10.09-20.32) nmol/mouse. The order of potency of the various Dyn A-related peptides and fragments in producing motor effects was Dyn A approximately Dyn A-(1-13) > [Ala1]Dyn A-(1-13) approximately Dyn A-(2-13) > alpha-Neo-End > Dyn A-(1-8) approximately Dyn B approximately Dyn A-(2-8) >>> Dyn A-(3-8). Dyn A-(1- 5) (or Leu-Enk) and Dyn A-(6-10) displayed no motor effect at doses up to 100 nmol/mouse. The potencies of Dyn A and Dyn A-(2-13) were not affected by preadministration of naloxone (5 mg/kg s.c.), but the motor effects of Dyn A-(1-13) (20 nmol/mouse i.c.v.) were significantly reduced by coadministration of low doses (0.2-0.6 nmol/mouse) of the N-methyl-D-aspartate (NMDA) receptor antagonists dextrorphan, MK-801 and CPP. Dyn A was also a potent inhibitor of the binding of the phencyclidine receptor ligand, [3H]MK-801, to rat brain membranes, with a Ki value of 0.41 microM. However, the order of potency of the various Dyn A-related peptides and fragments in inhibiting [3H]MK-801 binding did not correlate with their ability to produce motor effects. On the other hand, Dyn A and related peptides produced a significant potentiation of the binding of the competitive NMDA antagonist [3H]CGP-39653 to rat brain membranes, an effect that correlated well (r = 0.91) with their potency in producing motor effects. These results indicate that the nonopioid motor effects of Dyn A and related peptides are structure dependent, with Dyn A-(2-8) being the minimal core peptide for motor activity. In addition, these effects most likely involve the participation of the excitatory amino acid binding domain on the NMDA receptor complex.

2-Amino-5-phosphonovalerate↗
PubMed1995

Directed inactivation of the psbI gene does not affect photosystem II in the cyanobacterium Synechocystis sp. PCC 6803.

PsbI is a small, integral membrane protein component of photosystem II (PSII), a pigment-protein complex in cyanobacteria, algae and higher plants. To understand the function of this protein, we have isolated the psbI gene from the unicellular cyanobacterium Synechocystis sp. PCC 6803 and determined its nucleotide sequence. Using an antibiotic-resistance cartridge to disrupt and replace the psbI gene, we have created mutants of Synechocystis 6803 that lack the PsbI protein. Analysis of these mutants revealed that absence of the PsbI protein results in a 25-30% loss of PSII activity. However, other PSII polypeptides are present in near wild-type amounts, indicating that no significant destabilization of the PSII complex has occurred. These results contrast with recently reported data indicating that PsbI-deficient mutants of the eukaryotic alga Chlamydomonas reinhardtii are highly light-sensitive and have a significantly lower (80-90%) titer of the PSII complex. In Synechocystis 6803, PsbI-deficient cells appear to be slightly more photosensitive than wild-type cells, suggesting that this protein, while not essential for PSII biogenesis or function, plays a role in the optimization of PSII activity.

Amino Acid Sequence↗
PubMed1995

Pertussis and cholera toxins modulate kappa-opioid receptor agonists-induced hypothermia and gut inhibition.

In mice pretreated intracerebroventricularly (i.c.v.) with either saline (10 microliters/mouse), pertussis (1 microgram/mouse) or cholera (2.5 micrograms/mouse) toxins, effect of kappa-opioid receptor agonists on the colonic temperature and charcoal meal transit time were assessed. The kappa-opioid receptor agonist, trans-(+)-3,4-dichloro-N-methyl-[2-(1- pyrrolidinyl)cyclohexyl]-benzeneacetamide methane sulfonate hydrate (U-50488H, 50, 100 and 200 micrograms/mouse, i.c.v.) produced dose dependent hypothermia. Pertussis toxin pretreatment (72 and/or 144 h before) antagonized (P < 0.05) the hypothermic effect of U-50488H (100 micrograms/mouse) and (+)-trans-N-methyl-N-[2-(1- pyrrolidinyl)cyclohexyl[benz[b]-thio-phene-4-acetamide (PD 117302, 30 micrograms/mouse). In contrast, cholera toxin pretreatment (48 and/or 96 h before) did not antagonize the hypothermic effect of the kappa-opioid receptor agonists. Moreover, both i.c.v. and intrathecal (i.t.) administration of kappa-opioid receptor agonists, U-50488H, }[5R-(5 alpha,7 alpha,8 beta)]-(+/-)-N-methyl-N-[7-(1- pyrrolidinyl)-1-oxaspiro[4,5]dec-8-yl]-benzeneacetamide¿ (U-69593) and PD 117302, produced dose dependent inhibition of the charcoal meal transit. Cholera toxin pretreatment (48 and 96 h before) augmented (P < 0.05) the antitransit effect of i.c.v. administered U-50488H (100 micrograms/mouse), U-69593 (100 micrograms/mouse) and PD 117302 (50 micrograms/mouse). However, pertussis toxin pretreatment did not affect the gastrointestinal inhibitory effect of the kappa-opioid receptor agonists. The present results extend our previous results on the effect of kappa-selective agonists on gastrointestinal motility and indicate, like the prototype opiate agonist morphine, kappa-opioid receptor agonists are effective in inhibiting the gastrointestinal motility when administered either by intrathecal or intracerebroventricular routes.(ABSTRACT TRUNCATED AT 250 WORDS)

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1995

Histogranin, a modified histone H4 fragment endowed with N-methyl-D-aspartate antagonist and immunostimulatory activities.

Histogranin is a naturally-occurring pentadecapeptide with a structure 80% homologous with that a fragment-(86-100) of histone H4. First isolated from bovine adrenal medulla, the peptide was also shown to be present in the pituitary, brain, adrenal glands, blood plasma, lungs and spleen. At the subcellular level, histogranin is concentrated in secretory vesicles and it is released from perfused bovine adrenal glands 15-35 min after stimulation with carbamylcholine as opposed to catecholamines and [Leu5]enkephalin which are released immediately after stimulation. Rat brain membranes possess specific binding sites for [125I][Ser1]histogranin with characteristics of a receptor, namely high affinity, saturability, reversibility and sensitivity to heat and proteolytic enzyme treatments. Intracerebroventricular injections of synthetic histogranin (10-100 nmol) in mice protect them against N-methyl-D-aspartate (NMDA)-induced convulsions without affecting convulsions induced by (R,S)-alpha-amino-3-hydroxy -5-methyl-4-isoxazole-propionate (AMPA), kainate and bicuculline. The peptide also binds to specific sites on human peripheral blood mononuclear cells and it evokes the release of tumor necrosis factor-alpha (TNF), interleukin-1 (IL-1) and interleukin-6 (IL-6) from isolated rat macrophages in culture. Since the structure of histone H4 is considered as one of the most conservative, it is presumed that histogranin possesses its own precursor and that its gene is distinctly expressed.

Adjuvants, Immunologic↗
PubMed1995

Erythrocyte membrane fatty acid profile in patients with primary carcinoma of the gallbladder.

Erythrocyte fatty acids were determined in patients with gall stones and carcinoma of the gallbladder. Significantly low levels of myristic acid (P < 0.01) and stearic acid (P < 0.001) and significantly high levels of palmitoleic acid (P < 0.05) and oleic acid (P < 0.01) were observed in cancer patients. Arachidonic and linolenic acid were significantly high in gallstone patients, but there was no significant difference in the lauric acid and palmitic acid levels. Thus an altered lipid metabolism in cancer patients suggest existence of a possible association between gallstones, fatty acids, and carcinoma of the gallbladder.

Cholelithiasis↗
PubMed1995

N-methyl-D-aspartate receptor antagonist activity and phencyclidine-like behavioral effects of the pentadecapeptide, [Ser1]histogranin.

The behavioral and pharmacologic profiles of [Ser1]histogranin ([Ser1]HN) were assessed by monitoring its ability to displace the binding of the specific N-methyl-D-aspartate (NMDA) receptor ligand, [3H]CGP 39653, to block the convulsant effects of NMDA and other excitatory agents in mice, and to produce phencyclidine (PCP)-like behavioral effects in rats. The peptide potently inhibited [3H]CGP 39653 binding to membrane preparations of rat brain with an IC50 of 198 nM and a maximal inhibition of 34% of the specific binding activity. Saturation binding experiments with [3H]CGP 39653 in the absence and presence of [Ser1]HN (2 microM) indicated that the inhibitory effect of the peptide was noncompetititive, producing a decrease in the maximal number of binding sites (Bmax of 62.5 fmol/mg protein as compared with 91.3 fmol/mg protein in control), but no significant change in the affinity (Kd of 4.5 nM as compared with 5.1 nM in control). Intracerebroventricular (ICV) injection of [Ser1]HN (10-100 nmol) in mice evoked a dose-dependent and selective blockade of NMDA-induced convulsions. In rats, [Ser1]HN (2.5-100 nmol, ICV) produced dose-dependent stereotypy, ataxia, and locomotion similar to those observed with PCP, at doses ranging between 50 and 400 nmol. The data indicate that [Ser1]HN noncompetitively interacts with the NMDA receptor, an action that goes along with its in vivo NMDA receptor antagonist activity and PCP-like behavioral effects.

2-Amino-5-phosphonovalerate↗
PubMed1995

A case of squamous cell carcinoma complicating hidradenitis suppurativa.

A case of extensive squamous cell carcinoma arising in widespread perianal and inguinal hidradenitis suppurativa is used to illustrate the pathological features which influence management. The surgical pathology, with wide extension along subcutaneous sinuses, frequently leads to the view that it is incurable. A planned surgical approach, using both immediate frozen section and delayed paraffin histology to assess clearance margins allowed complete surgical excision in two stages. Colostomy is not a necessary part of management and healing by granulation is an acceptable alternative to extensive reconstruction procedures. Radiotherapy and chemotherapy, sometimes used in palliation mode, are not likely to be beneficial.

Aged↗
PubMed1995

Propofol modulates the effects of chemoconvulsants acting at GABAergic, glycinergic, and glutamate receptor subtypes.

BACKGROUND: Propofol has been used to treat status epilepticus, but its use in patients with seizure disorders remains controversial, because of concerns that it produces paroxysmal motor phenomenon. Chemoconvulsants act by known discrete mechanisms and neurotransmitters, and therefore, they are useful tools for screening anticonvulsant activity. The main objective of this study was to characterize the effect of propofol pretreatment on convulsions induced by picrotoxin, bicuculline, and strychnine, all which decrease inhibitory neurotransmission, and by N-methyl-D-aspartic acid, kainic acid, and quisqualic acid, which enhance excitatory neurotransmission. METHODS: Groups of male Swiss Webster mice (n > or = 10/group) were given either vehicle (intralipid, 10 ml.kg-1, control groups) or propofol (50 mg.kg-1, test groups) injected intraperitoneally. Five min after injection, convulsions were induced with either bicuculline (1.36-5.44 nmoles), picrotoxin (0.21-1 nmol), N-methyl-D-aspartic acid (0.51-2 nmol), quisqualic acid (1-10 nmol), kainic acid (0.252-2 mole), or strychnine (1.35-10.78 nmol) injected intracerebroventricularly. The number of animals with convulsions after each dose was recorded. Analysis of statistical significance was based on the log-probit lines of the quantal dose-response for the respective control and test groups, calculated 50% effective doses (ED50), the potency ratios (ED50higher/ED50lower) and their 95% confidence limits. RESULTS: Propofol pretreatment decreased the potency ratio of both bicuculline (0.47, 95% confidence interval = 0.23-0.94) and picrotoxin (0.61, 0.47-0.79), signifying an anticonvulsant effect. Conversely, propofol pretreatment significantly enhanced the convulsive potency of kainic acid (potency ratio and 95% confidence interval = 1.66, 1.21-2.29), quisqualic acid (3.17, 1.98-5.09), and strychnine (1.76, 0.79-3.89). CONCLUSIONS: Current results suggest that propofol augments the paroxysmal motor phenomenon induced by kainic acid, quisqualic acid, and strychnine. This action may be, at least partly, responsible for the motor manifestations reported after propofol administration. These in vivo results on modulation of gamma-aminobutyric acid, glycine, alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, and kainate receptor-mediated transmission may be of significance in understanding the mechanism of propofol action at the excitatory and inhibitory amino acid receptors.

Anesthetics, Intravenous↗
PubMed1995

Synthesis and biological activity of histogranin and related peptides.

Histogranin (HN) was first isolated from bovine adrenal medulla and shown to be a pentadecapeptide displaying N-methyl-D-aspartate (NMDA) receptor antagonist activity. To determine the active pharmacophore of HN, fragments of the peptide were synthesized and their structure-activity relationships studied by measuring their ability to displace the binding of [125I][Ser1]HN to rat brain membrane preparations and to block NMDA-induced convulsions in mice. In the binding assay, only the full length peptide HN and HN(1-10) displayed a high affinity (Ki of 72 and 162 nM, respectively). All other tested fragments with deletions at the N- and (or) C-terminals of the molecule showed large (16- to 2500-fold) decreases in potency. The least active peptide fragment tested was HN(6-10) (Ki of 164 microM). In vivo, HN and HN(2-15) (100 nmol; i.c.v.) produced 94 and 40% protection against NMDA-induced convulsions in mice, respectively. None of the other peptide fragments displayed significant anticonvulsant activity. The protective activity of HN (60 and 100 nmol) was markedly antagonized by coadministration of HN(1-10) (100 nmol). The results indicate that the in vivo anti-NMDA and in vitro binding activities of HN and related peptides, with the exception of HN(1-10), depend upon the integrity of the molecule. On the other hand, the high affinity of HN(1-10) for HN binding sites correlates well with its antagonist effects towards the activity of the parent peptide.

Animals↗