Biomedical subjects

J Singh

Publications and source records attributed to J Singh.

At least 253 records · Page 14Linked to original sources

PubMed1998

Sensitivity of poliomyelitis surveillance in India.

OBJECTIVE: To estimate the sensitivity of poliomyelitis surveillance in India. DESIGN: A comparison of two sets of data obtained from lameness surveys and routine surveillance system. METHODS: Lameness surveys were undertaken by the Ministry of Health and Family Welfare in 1981, 1989 and 1992 using 30-cluster sampling technique. These data were compared with the number of polio cases reported through routine surveillance system. RESULTS: Based on the 1981 survey which was undertaken near the initiation of routine immunization with oral polio vaccine (OPV) in India, poliomyelitis incidence was estimated at 25 cases per 100,000 population. Subsequent studies in 1989 and 1992 estimated a decrease in incidence rates to 15.7 and 6.3 cases per 100,000 population, respectively. Comparing the number of reported cases with the survey estimates provided a measure of the sensitivity of (completeness of reporting) surveillance; the sensitivity increased from 8% in 1981, to 20% in 1989, to 32% in 1992. CONCLUSION: The results are encouraging when compared with the global estimates of 10% reporting in 1993. Nevertheless, there is a need for further improvement in the completeness of reporting of poliomyelitis cases to detect all the cases of acute flaccid paralysis to allow epidemiological investigations and effective follow-up action which is critical to interrupt wild virus transmission.

Child↗

PubMed1998

Endemic cholera in Delhi, 1995: analysis of data from a sentinel centre.

Data on cholera cases admitted to the Delhi Infectious Diseases Hospital (IDH) are presented to describe the pattern of occurrence of cholera in Delhi in 1995. Rectal swabs from 4082 cases of acute diarrhoea admitted to the IDH were examined for excretion of Vibrio cholerae. Of them, 2004(49%) and 4(0.1%) were positive for V. cholerae O1 biotype El Tor and V. cholerae O139 respectively. Most cholera cases occurred during May-September (summer and monsoon months). The period from January to March (winter) was completely free from cholera. The urban areas were not affected uniformly. Of the 80 PIN (Postal Index Number) code areas, 10 contributed to 57% of the cases. The early cases were scattered in PIN code areas distant from one another. The hospitalisation rates for cholera were the highest in children aged less than five years and declined significantly with increasing patients' age. Males had significantly higher rates than females aged up to 20 years, whereas the situation was reversed in the 20 to 39 year age group. Four per cent of the affected families had multiple cases. An estimated 1% of the household contacts of hospitalised cases of cholera were themselves hospitalised for cholera within 2 days of the first admission. Of the 260 V. cholerae O1 isolates tested, 4%, 7%, 8%, 89%, 91% and 95% were resistant to tetracycline, nalidixic acid, chloramphenicol, co-trimoxazole, streptomycin, and furazolidone respectively. The study highlights the usefulness of surveillance data to identify groups, urban areas and seasons with increased risk for cholera and to allow control measures to be focussed on those in greatest need.

Adolescent↗

PubMed1997

Effects of extracellular Mg2+ concentration on intracellular signalling and acid secretion in rat gastric parietal cells.

In the present study, the effects of extracellular magnesium concentration ([Mg2+]ex) on stimulus-secretion coupling processes were investigated in rat gastric parietal cells in vitro. Extracellular magnesium reduction resulted in (1) an increase of basal intracellular free calcium concentration ([Ca2+]in), (2) an enhancement of both carbachol and thapsigargin-induced calcium responses, (3) an improved filling state of intracellular calcium stores, (4) an increase of both basal and carbachol-induced acid secretion, whereas intracellular adenosine 3',5'-cyclic monophosphate (cyclicAMP) levels and histamine stimulated acid secretion were not affected. The effects of high [Mg2+]ex were opposite to the described results, except that high [Mg2+]ex was able to decrease significantly histamine-stimulated cyclicAMP levels and acid secretion. These findings indicate a modulatory role of [Mg2+]ex on the intracellular signalling processes and acid secretory properties in rat parietal cells. These effects seemed to be mediated by regulating (1) calcium loading capacity of intracellular stores, (2) the permeability of the calcium influx pathway, and (3) the formation of cyclicAMP.

Animals↗

PubMed1997

Dietary fat and colon cancer: modulation of cyclooxygenase-2 by types and amount of dietary fat during the postinitiation stage of colon carcinogenesis.

Several epidemiological and experimental studies have indicated a strong relationship between different types of dietary fats and risk of colon cancer. However, the modulating effects of these nutritional factors at the molecular level are not fully elucidated. It has been documented that the modulation of tumorigenesis is associated with changes in the levels of prostaglandins production. To provide an understanding of the mechanism(s) of dietary fat-induced modulation of colon tumor development, we have analyzed the expression of cyclooxygenase (COX), an enzyme that catalyzes the metabolism of omega-3 and omega-6 polyunsaturated fatty acids in a critical step in prostaglandin biosynthesis. Male F344 rats were fed the semipurified AIN-76A diet containing low-fat corn oil and were s.c. injected azoxymethane (AOM) dissolved in normal saline at a dose rate of 15 mg/kg of body weight, once weekly, for 2 weeks. Vehicle controls received s.c. equal volumes of normal saline. One day after the second AOM or saline injection, rats intended to receive experimental diets were provided high-fat corn oil (HFCO) or high-fat fish oil (HFFO) mixed in semipurified AIN-76A diet, and the remaining rats continued to receive the low-fat corn oil diet. Animals were sacrificed 1, 12, or 36 weeks after the last AOM or saline injection, and their colonic mucosa, as well as the grossly visible colon tumors from rats sacrificed 36 weeks after the last AOM injection, were analyzed for the expression levels of COX-1 and COX-2. The results indicate that AOM induced increasingly high levels of COX-2 expression with advancing stages of colon tumorigenesis. HFCO further enhanced the AOM-induced COX-2 expression. In contrast, HFFO ingestion resulted in a significant decrease in COX-2 expression both in the colonic mucosa and in tumors. These results correlate with increased incidence and multiplicity of grossly visible colon tumors in AOM-treated animals that were fed the HFCO diet versus decreased tumor incidence and lower tumor multiplicity in animals that were fed the HFFO diet. No significant differences were observed in expression levels of COX-1. The data suggest that HFCO may promote colon tumorigenesis by up-regulating the COX-2 expression, whereas HFFO may exert its antitumor effect by inhibiting the COX-2 expression.

Animals↗

PubMed1997

Control of porcine lacrimal gland secretion by non-cholinergic, non-adrenergic nerves: effects of electrical field stimulation, VIP and NPY.

This study employs the technique of electrical field stimulation (EFS) to characterise the effects of endogenous neurotransmitters on protein secretion in the in vitro pig lacrimal gland. The effects of exogenous applications of neurotransmitters on protein output and peroxidase secretion were also investigated for comparative purposes. EFS evoked frequency-dependent (5-20 Hz) increases in protein secretion. The EFS-evoked protein output was abolished with the nerve blocking drug tetrodotoxin (10(-6) M, TTX). Elevated potassium (100 mM KCl) can stimulate protein output in the presence of TTX. Exogenous application of either acetylcholine (ACh, 10(-9)-10(-4) M) or noradrenaline (NA, 10(-8)-10(-4) M) can also result in protein secretion, but they have no detectable effect on peroxidase secretion. In the presence of the cholinergic antagonist, atropine (10(-5) M) the EFS-induced protein output was reduced but not abolished. This atropine-resistant and non-cholinergic nerve-mediated component was further reduced in the combined presence of atropine, phentolamine, and propranolol (all 10(-5) M). When vasoactive intestinal polypeptide (VIP) receptor antagonist (10(-6) M [4-Cl-D-Phe6-Leu17]-VIP) was combined with the cholinergic and adrenergic antagonists, EFS caused a small but detectable increase in protein output. Exogenous application of either 10(-9) M VIP or 10(-9) M neuropeptide-Y (NPY) resulted in protein secretion. Combination of both VIP and NPY only induced an additive effect on protein output. Theophylline (10(-4) M), a phosphodiesterase inhibitor, evoked a small increase in protein output and had no significant effect on the secretory responses elicited by either VIP or NPY. In contrast, theophylline potentiated the non-cholinergic, non-adrenergic EFS-induced protein secretion. The results indicate that protein secretion from the porcine lacrimal gland may be controlled by cholinergic, adrenergic and non-cholinergic, non-adrenergic nerves. The peptidergic neurotransmitters may be VIP and other related neuropeptide(s). In addition to these neurophysiological studies, our results confirm previous findings that the porcine lacrimal nerves contain abundant quantity of NPY and VIP.

Acetylcholine↗

PubMed1997

Structure-based design of a potent, selective, and irreversible inhibitor of the catalytic domain of the erbB receptor subfamily of protein tyrosine kinases.

We report the use of structure-based drug design to create a selective erbB-1 (a.k.a. epidermal growth factor receptor) and erbB-2 (a.k.a. neu/her2 growth factor receptor) tyrosine kinase inhibitor. Using the X-ray crystal structure of the ternary complex of the cAMP-dependent Ser/Thr kinase together with a sequence alignment of the catalytic domains of a representative set of Ser/Thr and Tyr protein kinases, we have examined the nucleotide binding site for potential positions to attach an irreversible inhibitor. This information, combined with homology modeling of the erbB-1 and erbB-2 tyrosine kinase catalytic domains, has led to the identification of Cys797 of erbB1 and Cys805 of erbB2, which are structurally equivalent to Glu127 in the cAMP dependant Ser/Thr kinase as potential target residues. The X-ray structure of the cAMP Ser/Thr kinase shows Glu127 to be involved in a hydrogen-bonding interaction with the 2'-OH of the ribose portion of ATP. Using molecular modeling, it was predicted that the Cys side chains in erbB-1 and erbB-2 performed an analogous role, and it was postulated that the replacement of the 2'-OH of adenosine with a thiol might allow for a covalent bond to form. Since only erbB-1 and erbB-2 have a Cys at this position, the inhibitor should be selective. This model was subsequently tested experimentally by chemical synthesis of 2'-thioadenosine and assayed against the full length erbB-1 receptor and the catalytic domains of erbB-2, insulin receptor, beta-PDGF receptor, and the FGF receptor. Our results show that thioadenosine covalently inactivates erbB-1 with a second-order rate constant of k(max)/K(S) = 2000 +/- 500 M(-1) s(-1). Inactivation is fully reversed by 1 mM dithiothreitol, suggesting that inactivation involves the modification of a cysteine residue at the active site, presumably Cys797. The rate of inactivation saturates with increasing thioadenosine concentrations, suggesting that inactivation occurs through initial formation of a noncovalent complex with K(D) = 1.0 +/- 0.3 microM, followed by the slow formation of a disulfide bond with a rate constant of k(max) = (2.3 +/- 0.2) x 10(-3) s(-1). This approach may have application in the design of selective irreversible inhibitors against other members of the kinase family.

Amino Acid Sequence↗

PubMed1997

Does receptor-'Ck' deficiency initiate leukaemia?

We have developed a polyclonal monospecific antibody (designated Ab-Ck) which recognises specifically a novel cell surface Receptor-'Ck', having inherent ability to regulate mevalonate pathway that is vital for many cellular functions ranging from growth control to differentiation. By using this 'Ab-Ck' as a probe, the Western blot analysis of protein fractions derived from various types of normal and cancerous cells/tissues revealed not only that this Receptor-'Ck' was ubiquitously present in various human organs, especially adrenal cortex, aorta, liver and brain, but also that leukaemic cell lines as well as lymphocytes from CML patients were specifically and selectively deficient in this receptor. Based upon these observations, we propose that leukaemic process may be initiated as a consequence of the deficiency of this novel Receptor-'Ck'.

Antibodies↗

PubMed1997

Dietary fat and colon cancer: modulating effect of types and amount of dietary fat on ras-p21 function during promotion and progression stages of colon cancer.

Although epidemiological and experimental studies have indicated a strong relationship between types and amount of dietary fat and colon tumorigenesis, the modulating effects of these nutritional factors at the molecular level have not been fully elucidated. Transforming proteins encoded by activated ras genes have been implicated in the etiology of many human malignancies, including colon cancer. It is now well established that the transforming ability of ras-p21 critically depends on its correct localization in plasma membrane. The posttranslational processing of the cytosolic precursor (pro-ras), as it is synthesized in the cytoplasm, and its proper anchorage to the cytoplasmic face of plasma membrane are determined by an important intermediate metabolite of dietary fat and an enzyme system that includes farnesyl protein transferase. To provide an understanding of the molecular basis of the relationship between the types and amount of dietary fat and the transforming function of ras, especially during the stages of promotion and progression of colon tumor development, we investigated the effect of various types and amount of dietary fat on the expression of ras-p21 during azoxymethane (AOM)-induced colon carcinogenesis. Male F344 rats were fed the semipurified American Institute of Nutrition-76A diet containing low-fat corn oil and were given s.c. injections of AOM dissolved in normal saline at a dose rate of 15 mg/kg body weight, once weekly, for 2 weeks. Control animals received s.c. injections of equal volumes of normal saline. Beginning 1 day after the second AOM or saline injection, groups of animals intended for the treatment with different types of high-fat dietary regimens were fed the semipurified American Institute of Nutrition-76A diets containing high levels of high-fat corn oil (HFCO) rich in omega-6 fatty acids or high levels of high-fat fish oil (HFFO) rich in omega-3 fatty acids; the remaining animals in experimental and control groups were continued on the low-fat corn oil diet until termination of the experiment. Groups of animals were sacrificed 1, 12, or 36 weeks after the last AOM or saline injection, and their colonic mucosa and grossly visible colon tumors from rats sacrificed 36 weeks after the last AOM injection were analyzed for the levels of expression of ras-p21. We found that AOM induced increasingly higher levels of ras-p21 expression with advancing stages of colon tumor development. The HFCO diet resulted in enhanced expression of AOM-induced ras-p21 as observed 36 weeks after the last AOM injection. In contrast, feeding the HFFO diet inhibited AOM-induced ras-p21 expression. These results correlate with increased incidence and multiplicity of grossly visible colon tumors in AOM-treated animals fed a HFCO diet versus decreased incidence and lower multiplicity of colon tumors in their counterparts on the HFFO diet. Further analysis of ras-p21 levels in cytosol and plasma membrane revealed that feeding a HFFO diet resulted in increasing accumulation of ras-p21 in cytoplasm with a concomitant decrease in membrane-bound ras-p21 levels as observed in animals sacrificed 12 and 36 weeks after the last AOM injection. Thus, the dietary HFCO may promote colon tumorigenesis by increasing ras-p21 expression, whereas HFFO appears to exert its antitumor activity by interfering with posttranslational modification and membrane localization of ras-p21.

Animals↗

PubMed1997

Pharmacokinetics and pharmacodynamics of 15-deoxyspergualin in a canine renal allograft model of local immunosuppression.

Local immunosuppression is based on the rationale that one can simultaneously prevent rejection and reduce systemic side effects by administering appropriately chosen immunosuppressive agents directly into the allograft. We utilized a mongrel canine renal transplant model with a programmable, implantable pump/catheter system to estimate the first-pass extraction of 15-deoxyspergualin (DSG) during renal artery infusion and to compare the efficacy and toxicity of continuous intraarterial (ia) versus intravenous (iv) DSG delivery. Six autotransplanted dogs were given DSG by both iv bolus (1 mg/kg) and ia infusion (1.0 mg/kg/d). DSG was administered to allograft recipients by continuous ia infusion at 0.5 (n = 11) and 0.75 (n = 8) mg/kg/day and by continuous iv infusion at 0.5 (n = 12) and 0.75 (n = 6) mg/kg/day. Mean +/- SD elimination half-life was 0.6 +/- 0.1 hr, and the transplanted kidney removed as much as 55-88% (mean 66%) of locally infused DSG. When compared with untreated controls [mean survival time (MST) = 8 days], low-dose (0. 5 mg/kg/day) DSG produced a significant antirejection effect when given ia (MST = 12 days; P = 0.04) but not iv (MST = 9 days; P = 0. 09), with equivalent overall mean drug levels during normal renal function. However, two of the four longest-surviving animals in the ia group died from severe systemic toxicity, manifested by anorexia, diarrhea, leukopenia, and sepsis. High-dose (0.75 mg/kg/day) DSG significantly prolonged survival via both local (MST = 12 days; P = 0.04) and systemic (MST = 11 days; P = 0.02) routes, but half of the iv-treated dogs died from, and four of the longer-surviving ia-treated animals manifested signs of, systemic toxicity, with significantly higher mean drug levels in the iv group. DSG significantly suppressed vascular rejection at both doses when administered locally and systemically, dose-dependently affected the severity of tubulointerstitial rejection and graft edema, and was not nephrotoxic. Our autotransplant pharmacokinetic data overestimated the allografted kidney's ability to extract DSG during local infusion of slightly lower, but immunosuppressive, doses, so that death from systemic toxicity was not prevented and a direct survival benefit of ia vs iv therapy was not realized. Local DSG administration might be combined with other immunosuppressants to therapeutic advantage.

Animals↗

PubMed1997

The physiological role of histamine in the exocrine pancreas.

In addition to the autonomic nervous system and gut hormones, the mast cell mediator histamine has also been associated with exocrine pancreatic secretion. This review is concerned with the distribution and the physiological role of histamine in the control of pancreatic juice secretion. Histamine is distributed widely around blood vessels and acinar tissues in the pancreas and it is released in pancreatic juice during secretagogue stimulation. Histamine has a marked secretagogue effect in the exocrine pancreas of several animal species but in many cases the secretory effect is gender-related. The paracrine hormone exerts its secretory response via activation of H1 and H2 receptors on pancreatic acinar cells to mobilize potassium ions (K+) and cellular calcium (Ca2+) and through elevation of endogenous adenosine 3',5' cyclic monophosphate (cyclic AMP) levels, respectively. A physiological role for H3 receptors has also been associated with exocrine pancreatic secretion. H3 receptors are located presynaptically on parasympathetic nerve terminals to control the release of acetylcholine via restriction of Ca2+ access into nerve terminal through the N-type Ca2+ channel. Taken together, the results presented in this review strongly support histamine as a potential modulator of exocrine pancreatic function.

Animals↗

PubMed1997

Cholinergic and GABAergic modulation of self-stimulation of lateral hypothalamus and ventral tegmentum: effects of carbachol, atropine, bicuculline, and picrotoxin.

This study aimed at investigating the effects of modulators of acetylcholine-muscarinic (ACh-M) and GABAA.B-receptors in the lateral hypothalamus and ventral tegmentum on the electrical self-stimulation evoked from these regions. In each Wistar rat, a bipolar electrode and an ipsilateral insulated cannula-cum-electrode were implanted chronically in the right hemisphere. There were two placement combinations: 1. Bipolar electrode in lateral hypothalamus-medial forebrain bundle (LH-MFB) and cannulacum-electrode in ventral tegmental area-substantia nigra (VTA-SN) or 2, bipolar electrode in VTA-SN and cannula-cum-electrode in LH-MFB. The stimulation parameters were kept at a level to obtain 50% of the maximum possible asymptotic intracranial self-stimulation (ICSS) rates (M50) from each site. Carbachol injected into VTA-SN increased the ICSS responding rate of VTA-SN as well as, indirectly, that of LH-MFB, and atropine injections had an opposite effect. Similar injections of these ligands into LH-MFB again had facilitatory and inhibitory effects on its ICSS: however, there was no indirect effect on the ICSS of VTA-SN. Bicuculline injection into VTA-SN had no effect on either its ICSS or that of LH-MFB. On the other hand, bicuculline injected into LH-MFB decreased its ICSS and, indirectly, the ICSS of VTA-SN in a dose-dependent manner. In contrast, intra VTA-SN injections of picrotoxin decreased its ICSS and, indirectly, ICSS of LH-MFB. Similar injections into LH-MFB had no effect on the ICSS of VTA-SN. The results suggest that ICSS of VTA-SN is Ach-M receptor mediated and, also, this mediation influences the ICSS of LH-MFB. On the contrary, changes in ICSS of LH-MFB following Ach-M receptor ligands do not influence the ICSS of VTA-SN. The direct effects of GABA-receptor antagonists have shown disassociation because ICSS of LH-MFB was more sensitive to bicuculline, whereas the ICSS of VTA-SN was more sensitive to picrotoxin. Thus, the cholinergic and GABAergic mechanisms of the self-stimulation of lateral hypothalamus and ventral tegmentum are different.

Animals↗

PubMed1997

Effects of microinjections of cholecystokinin and neurotensin into lateral hypothalamus and ventral mesencephalon on intracranial self-stimulation.

Changes in intracranial self-stimulation (ICSS) evoked from ventral tegmental area-substantia nigra (VTA-SN) and lateral hypothalamus-medial forebrain bundle (LH-MFB) before and after microinjections of sulfated cholecystokinin octapeptide (CCK-8S) and unsulfated cholecystokinin (CCK-8US), neurotensin tridecapeptide ([D-Tyr11]NT(1-13) or [DTrp11]NT(1-13)) into either VTA-SN or LH-MFB were assessed. The current intensity was fixed at a level to obtain 60-70% of the maximal asymptotic rate. CCK-8S (0.10 microg/0.5 microl and 0.25 microg/0.5 microl) into VTA-SN resulted in dose-dependent decreases in VTA-SN ICSS of 38-42% and 78-92%, respectively, without affecting the ICSS of LH-MFB. Similar doses of CCK-8S injected into LH-MFB changed neither LH-MFB ICSS nor VTA-SN ICSS. CCK-8Us injected into VTA-SN or LH-MFB had no effect on ICSS in either site. Intra-VTA-SN injections of the neurotensin-1 (NT1) receptor agonist [DTyr11]NT(1-13) and the NT1 receptor antagonist [D-Trp11]NT(1-13) at doses of 5 microg/0.5 microl and 10 microg/0.5 microl decreased VTA-SN ICSS. NT1 receptor agonist and antagonist injections did not alter LH-MFB ICSS in any significant manner. Similar injections of these peptides into LH-MFB did not change the responding rates for LH-MFB ICSS or VTA-SN ICSS. Increasing the current intensity reversed the inhibitory effect of CCK-8S and [D-Trp11]NT(1-13) on VTA-SN ICSS and restored basal preinjection rates of responding. These results suggest that CCK(A) and NT1 receptor mechanisms in the ventral tegmentum in association with dopamine neurotransmission may be important in mediating the rewarding effects of VTA-SN ICSS but not LH-MFB ICSS.

Animals↗

PubMed1997

Dopamine receptor sub-types involvement in nucleus accumbens and ventral tegmentum but not in medial prefrontal cortex: on self-stimulation of lateral hypothalamus and ventral mesencephalon.

The involvement of different sub-types of dopamine receptors in the electrical self-stimulation behaviour was investigated using DA receptor subtype specific agonists viz R(+) SKF 38393 and LY 171555 (quinipirole). Rats were chronically implanted with bipolar electrodes in lateral hypothalamus-medial forebrain bundles (LH-MFB) and ventral tegmental area-substantia nigra (VTA-SN) or guide cannula in nucleus accumbens (nACB) or medial prefrontal cortex (mPFRCx) or cannula-cum-electrode in VTA-SN. Combining these, it was possible to inject a given receptor ligand in either nACB or mPFRCx or VTA-SN and assess the changes in intracranial self-stimulation (ICSS) of LH-MFB or VTA-SN. The experimental subjects were trained to press a pedal to obtain 0.25 s trains of cathodal rectangular pulses of 0.1 ms pulse duration (for LH-MFB electrode) or 0.3 ms pulse duration (for VTA-SN electrode). The rate-frequency curve for each subject and each placement were obtained in order to determine M50 (50% of maximum asymptotic response rate). Microinjection of SKF 38393 (a D1 agonist) or LY 171555 (a D2 agonist) into nACB caused facilitatory and suppressive effects on the ICSS of VTA-SN and LH-MFB respectively. On the contrary, intra VTA-SN injection of 10 micrograms/0.5 microliter of SKF 38393 or of LY 171555, reduced its ICSS to half as compared to vehicle injections. Under the effect of these injections, there was no change in the ICSS of LH-MFB. The combined administration of SKF 38393 (5 micrograms) and LY 171555 (10 micrograms) into nACB produced suppression of ICSS of VTA-SN to greater extent than the LY 171555 (10 micrograms/0.5 microliter). This indicates that coactivation of D1 and D2 leads to suppression of ICSS of VTA-SN. The activation of D1 receptors in nACB facilitates the ICSS of both VTA-SN and LH-MFB by increasing the reinforcement and/locomotor activity, while the activation of D2 receptors in it has opposite effect. The coactivation of D1 and D2 receptors in VTA-SN leads to the suppression of ICSS of both VTA-SN and LH-MFB. Similar injections of these receptor ligands into mPFRCx did not alter the ICSS of either LH-MFB or VTA-SN. The pre- or post-synaptic DA receptors of mPFRCx do not appear to influence the ICSS of either VTA-SN or LH-MFB in any significant manner.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗

PubMed1997

Macrophages/microglia as 'sensors' of injury in the pineal gland of rats following a non-penetrative blast.

The pineal gland of adult rats was examined immunohistochemically and electron microscopically following exposure of the animals to a single blast equivalent to 110 kg TNT explosive. The most dramatic feature in rats killed at 7, 14 and 21 days after the blast was the upsurge of a large number of macrophages/microglia intensely immunostained with OX-42, OX-18, OX-6 and ED1 antibodies. These antibodies recognise the complement type three (CR3) receptors, major histocompatibility complex class I and class II (MHC I and MHC II) antigens and monocyte/macrophage antigens. Cell counts in OX-42 immunostained sections showed a two-fold increase at these intervals but returned to normal values at 28 days. The immunolabelled cells appeared extremely hypertrophic after the blast when compared with those in normal rats. In the latter and in rats killed at 28 days after the blast, immunoreactive cells were sparsely distributed. Ultrastructural study confirmed a wider occurrence of perivascular macrophages/microglia after the blast and the cells were laden with massive amounts of phagosomes resembling degenerating pinealocyte processes. It is concluded that the seemingly quiescent macrophages/microglia present normally in pineal gland were activated by the external blast force. The induced changes including the increase in cell numbers and endocytosis, however, were reversible in longer surviving animals.

Animals↗

PubMed1997

Interactions of islet hormones with acetylcholine in the isolated rat pancreas.

This study investigates the effects of the islet hormones, insulin (INS), glucagon (GLU) and somatostatin (SOM) on acetylcholine (ACh)-evoked amylase secretion and calcium (Ca2+) mobilization in the isolated rat pancreas. Stimulation of pancreatic segments and acini with either INS, GLU or SOM resulted in small increases of amylase output compared to much large increases in enzyme output with ACh. Combinations of the peptide hormones with ACh resulted in enhanced secretory responses compared to the effects obtained with either ACh or each of the islet hormone alone. Genistein, the tyrosine kinase inhibitor, evoked a decrease in amylase output from pancreatic segments. It had no effect on the ACh evoke secretory response but it markedly inhibited the potentiation of the islet hormones with ACh. In pancreatic acinar cells either INS, GLU or SOM elicited moderate increases in amylase output compared to much larger responses with ACh. Furthermore, the islet hormones failed to potentiate the secretory effect of ACh in pancreatic acini. In fura-2 AM loaded acinar cells both INS and GLU evoked small increases in intracellular free calcium concentration [Ca2+]i compared to a much larger elevation with ACh. Both INS and GLU enhanced the ACh-evoked [Ca2+]i. Genistein elicited a decrease in [Ca2+]i both in the absence and presence of both INS and GLU. It also decreased the rise in [Ca2+]i resulting from the combined presence of ACh with both INS and GLU. SOM had no significant effect on the ACh-induced [Ca2+]i. When genistein was combined with ACh and SOM there was a decrease in [Ca2+]i compared to the response obtained with SOM and ACh alone. The results indicate that both tyrosine kinase and cellular Ca2+ seem to be the intracellular mediators associated with the enhanced secretory responses obtained with a combination of the islet hormones with ACh. Finally, our results using immunohistochemical techniques confirm the presence of INS-, GLU- SOM- and ACh-immunoreactive cells in the endocrine and neural elements of the rat pancreas.

Acetylcholine↗

PubMed1997

Removal of TNT and RDX from water and soil using iron metal.

Contaminated water and soil at active or abandoned munitions plants is a serious problem since these compounds pose risks to human health and can be toxic to aquatic and terrestrial life. Our objective was to determine if zero-valent iron (Fe(0)) could be used to promote remediation of water and soil contaminated with 2,4,6-trinitrotoluene (TNT) and hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX). As little as 1% Fe(0) (w/v) removed 70 mg TNT litre(-1) from aqueous solution within 8 h and removed 32 mg RDX litre(-1) within 96 h. Treating slurries (1:5 soil:water) of highly contaminated soil (5200 mg TNT and 6400 mg RDX kg(-1) soil) from the former Nebraska Ordnance Plant (NOP) with 10% Fe(0) (w/w soil) reduced CH(3)CN-extractable TNT and RDX concentrations below USEPA remediation goals (17.2 mg TNT and 5.8 mg RDX kg(-1)). Sequential treatment of a TNT-contaminated solution (70 mg TNT litre(-1) spiked with (14)C-TNT) with Fe(0) (5% w/v) followed by H(2)O(2) (1% v/v) completely destroyed TNT and removed about 94% of the (14)C from solution, 48% of which was mineralized to (14)CO(2) within 8 h. Fe(0)-treated TNT also was more susceptible to biological mineralization. Our observations indicate that Fe(0) alone, Fe(0) followed by H(2)O(2), or Fe(0) in combination with biotic treatment can be used for effective remediation of munitions-contaminated water and soil.

Journal Article↗

PubMed1997

Piperine inhibits aflatoxin B1-induced cytotoxicity and genotoxicity in V79 Chinese hamster cells genetically engineered to express rat cytochrome P4502B1.

We have investigated the potential of piperine for inhibiting the activity of cytochrome P4502B1 and protecting against aflatoxin B1 (AFB1) in V79MZr2B1 (r2B1) cells, i.e. V79 Chinese hamster cells engineered for the expression of rat CYP4502B1. The cells were found to contain high activities of 7-methoxycoumarin demethylase (MOCD). Piperine inhibited MOCD in preparations of r2B1 cells with an IC50 of approximately 10 microM. The cells in culture dealkylated 7-methoxycoumarin (MOC) to 7-OH-coumarin linearly, at least for 12 h, where piperine produced concentration-dependent inhibition with IC50 < 30 microM. The time required for maximal inhibition was approximately 8 h with both 30 and 60 microM concentrations of piperine used. AFB1 at 0.1-20 microM caused a concentration dependent decrease in the amount of DNA and an increase in the formation of micronuclei (MN). The mycotoxin at 10 microM reduced DNA by approximately 30% and increased MN appearance by 20-fold against the background level of 7 MN per 500 nuclei. Piperine at 60 microM completely counteracted cytotoxicity and formation of MN by 10 microM AFB1 and reduced the toxic effects of 20 microM AFB1 by > 50%. The results suggest that: (i) Piperine is a potent inhibitor of rat CYP4502B1 activity; (ii) AFB1 is activated by r2B1 cells to cytotoxic and genotoxic metabolites; and (iii) piperine counteracts CYP4502B1 mediated toxicity of AFB1 in the cells and might, therefore, offer a potent chemopreventive effect against procarcinogens activated by CYP4502B1.

Aflatoxin B1↗

PubMed1997

Protective actions of a thromboxane receptor antagonist, SQ 29548 on the ischemic myocardium: morphologic and hemodynamic effects.

The effects of thromboxane A2 (TXA2)/prostaglandin endoperoxide receptor blockade on myocardial infarct size and cardiac dynamics were determined in a canine model of 24 h acute myocardial infarction. Anesthetized open-chest dogs were subjected to left anterior descending (LAD) coronary artery occlusion. Twenty minutes post-occlusion the dogs were given i.v. saline (0.9% NaCl solution) (n = 12) or the TXA2 receptor antagonist SQ 29548 (0.2 mg/kg i.v. loading dose +0.2 mg/kg/h i.v. for 4 h) (n = 10). SQ 29548 treatment resulted in a significant (P < 0.01) reduction in infarct size. Heart rate (HR) and systolic blood pressure (SAP) were not markedly affected by the drug. The sharp rise in the left ventricular end diastolic pressure (LVEDP) in the saline-treated animals was significantly lowered by SQ 29548 treatment and the correction of this variable was maintained till 24 h post-occlusion. The lowered maximal rate of rise of left ventricular pressure (LVdP/dt max) in the saline-treated animals was corrected albeit non-significantly by the drug treatment. Thus, SQ 29548 treatment resulted in a significant salvage of myocardial tissue and marked alterations in left ventricular dynamics. The study suggests a deleterious role for thromboxane A2 in ischemia; indicating that TXA2 blockade may have potential as a mode of therapy for ischemic heart disease.

Animals↗