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Biomedical subjects

A Paul

Publications and source records attributed to A Paul.

At least 19 recordsLinked to original sources
PubMed1997

Stress-activated protein kinases: activation, regulation and function.

The response of cells to extracellular stimuli is mediated in part by a number of intracellular kinase and phosphatase enzymes. Within this area of research the activation of the p42 and p44 isoforms of mitogen-activated protein (MAP) kinases have been extensively described and characterised as central components of the signal transduction pathways stimulated by both growth factors and G-protein-coupled receptor agonists. Signaling events mediated by these kinases are fundamental to cellular functions such as proliferation and differentiation. More recently, homologues of the p42 and p44 isoforms of MAP kinase have been described, namely the stress-activated protein kinases (SAPKs) or alternatively the c-jun N-terminal kinases (JNKs) and p38 MAP kinase (the mammalian homologue of yeast HOG1). These MAP kinase homologues are integral components of parallel MAP kinase cascades activated in response to a number of cellular stresses including inflammatory cytokines (e.g., Interleukin-1 (Il-1) and tumour necrosis factor-alpha (TNF-alpha), heat and chemical shock, bacterial endotoxin and ischaemia/cellular ATP depletion. Activation of these MAP kinase homologues mediates the transduction of extracellular signals to the nucleus and are pivotal events in the regulation of the transcription events that determine functional outcome in response to such stresses. In this review we highlight the identification and characterisation of the stress-activated MAP kinase homologues, their role as components of parallel MAP kinase pathways and the regulation of cellular responses following exposure to cellular stress.

Animals↗
PubMed1997

Epilepsy or stereotypy? Diagnostic issues in learning disabilities.

Approximately 0.8% of people in the general population have epilepsy. Within this group are specific sub-populations who co-present with other additional conditions, learning disability being one such example. Epilepsy rates are the highest of all in this subgroup, between 21% and 50% and positively correlated with degree of learning disability. In addition, in the more severe categories, problems frequently arise when attempting to differentiate epileptic events from other phenomenon, such as stereotyped behaviours and involuntary movements. The individual is unable to communicate changes in consciousness and perception and observers often find it difficult to detect such changes, particularly with regard to the partial epilepsies. Intensive monitoring using EEG and video equipment can often prove valuable in such a situation in assisting carers to recognize epileptic episodes and respond accordingly.

Adult↗
PubMed1997

Differential regulation by protein kinase C isoforms of nitric oxide synthase induction in RAW 264.7 macrophages and rat aortic smooth muscle cells.

1. In RAW 264.7 murine macrophages and rat aortic smooth muscle (RASM) cells lipopolysaccharide (LPS) alone or in combination with interferon gamma (IFN gamma) or forskolin, respectively, stimulated the expression of the 130 kDa inducible isoform of nitric oxide synthase (iNOS) in both a time- and concentration-dependent manner. 2. Incubation with the direct activator of protein kinase C (PKC), phorbol 12-myristate 13-acetate (PMA) alone, did not result in detectable iNOS expression in either cell type. 3. Chronic PMA pretreatment resulted in significant down-regulation of alpha, beta and epsilon isforms of PKC in RAW 264.7 macrophages and corresponded to a 20-30% reduction in LPS-induced iNOS expression. In contrast, IFN gamma alone or in combination with LPS stimulated an approximate 20% and 50% potentiation, respectively. 4. Pre-incubation with PKC inhibitors (calphostin C and H-7) showed similar effects upon stimulated induction of iNOS. 5. In RASM cells chronic PMA pretreatment resulted in down-regulation of alpha and epsilon PKC isoforms and corresponded to potentiation of iNOS expression in response to LPS alone or in combination with forskolin. 6. Co-incubation of RASM cells in the presence of PMA, angiotensin II (AII) or foetal calf serum (FCS) resulted in the inhibition of iNOS expression in response to LPS alone or in combination with forskolin. 7. Differential sensitivity to PKC inhibitors (calphostin C and H-7) was observed in RASM cells and exhibited both negative and positive modulation of stimulated induction. 8. In addition the PKC inhibitor compound Ro-31-8220 abolished stimulated induction in both cell types in response to all treatments. 9. These results suggest that PKC activation is required for induction of the 130 kDa isoform of NOS in both RAW 264.7 macrophages and RASM cells. However, individual PKC isoforms regulate iNOS expression in both a positive and negative manner.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1997

Dissociation of lipopolysaccharide-mediated induction of nitric oxide synthase and inhibition of DNA synthesis in RAW 264.7 macrophages and rat aortic smooth muscle cells.

1. The active component of endotoxin, lipopolysaccharide (LPS), inhibited basal DNA synthesis in both RAW 264.7 macrophages (IC50 0.05 +/- 0.03 microgram ml-1) and rat aortic smooth muscle cells (RASMC) (IC50 9.7 +/- 0.4 micrograms ml-1). 2. In both cell types, serum differentially affected LPS-stimulated inhibition of DNA synthesis. In RAW 264.7 macrophages the presence of serum reduced the IC50 for LPS-stimulated inhibition of DNA synthesis (1.4 +/- 0.85 ng ml-1). However, in RASMC serum stimulated DNA synthesis and further increased the IC50 value for LPS-stimulated inhibition of thymidine incorporation (57.3 +/- 7.8 micrograms ml-1). 3. LPS also stimulated the induction of nitric oxide synthase (NOS) in RAW 264.7 macrophages with maximal expression at concentrations of 1-3 micrograms ml-1. This was wholly dependent upon the presence of serum. In RASMC LPS alone, up to concentrations of 100 micrograms ml-1, did not induce nitric oxide synthase and required co-incubation with the direct activator of adenylyl cyclase, forskolin. Under these conditions stimulated expression of NOS was inhibited by the presence of serum. 4. Incubation with the nitric oxide synthase inhibitors N omega-nitro-L-arginine methyl ester (L-NAME) and L-canavanine did not reverse the inhibition of [3H]-thymidine incorporation in response to LPS but prevented the formation of nitrite in both cell types. 5. These results indicate that the effects of LPS upon cell growth are independent of the induction of the 130 kDa isoform of nitric oxide synthase and nitric oxide formation in both RAW 264.7 macrophages and RASMC.

Animals↗
PubMed1997

Regulation of mucin secretion in human gallbladder epithelial cells: predominant role of calcium and protein kinase C.

BACKGROUND & AIMS: The cellular mechanisms that regulate biliary mucin secretion in humans are unknown. To address this question, human gallbladder epithelial cells were used in primary culture. METHODS: [1-(14)C]-glucosamine-labeled glycoproteins secreted in vitro were analyzed and quantified after exposing cells to activators and inhibitors of the main transduction pathways and to potential biologically active secretagogues. RESULTS: Secreted glycoproteins showed characteristics of biliary mucins. Activators of adenosine 3',5'-cyclic monophosphate-dependent pathway as well as secretin and vasoactive intestinal polypeptide did not significantly modify mucin secretion. By contrast, ionomycin and phorbol-12-myristate 13-acetate increased mucin secretion by 292% +/- 48% and 134% +/- 19% over basal level, respectively. The effects of these two agents were additive and were mediated by a calcium-dependent pathway implicating Ca2+/calmodulin-dependent protein kinase II (Ca2+/CaM-kinase II) and by the activation of protein kinase C (PKC), respectively, as ascertained by using inhibitors. Mucin secretion was stimulated by extracellular adenosine 5'-triphosphate via P2U receptors, cytosolic calcium increase, and PKC and by taurochenodeoxycholate via cytosolic calcium increase and Ca2+/CaM-kinase II. CONCLUSIONS: Mucin secretion in human gallbladder is regulated predominantly by calcium-dependent pathways implicating Ca2+/CaM-kinase II and PKC. Extracellular adenosine 5'-triphosphate and taurochenodeoxycholate may play a role in the regulation of biliary mucin secretion by activating these different signaling pathways.

Adenosine Triphosphate↗
PubMed1997

Gabapentin and cognition: a double blind, dose ranging, placebo controlled study in refractory epilepsy.

OBJECTIVE: To assess the effect of different doses of gabapentin (GBP) on cognitive function in treated epileptic patients. METHODS: Twenty seven patients with refractory partial seizures commenced a double blind, dose ranging, placebo controlled, crossover study of adjuvant GBP. Each treatment phase lasted three months, during which the dose of GBP or matched placebo was increased stepwise at intervals of four weeks (1200 mg/day, 1800 mg/day, and 2400 mg/day in three daily doses). Psychomotor and memory testing was carried out at the end of each four week period, at which time the patient also completed subjective measures of cognition, fatigue, worry, temper, and dysphoria. A visual analogue scale was used to assess drowsiness and a questionnaire was employed to gauge the severity of side effects. RESULTS: In the 21 patients completing the study, GBP produced a significant reduction in median monthly seizure frequency from 7 to 4.3 (P = 0.02), the decrease being most pronounced for secondarily generalised seizures (from 1.0 to 0.3, P = 0.01). Forty three per cent of patients reported a reduction in seizure frequency of at least 50% throughout all GBP doses. Mean (SD) plasma concentrations of GBP at 1200, 1800, and 2400 mg/day were 4.7 (2.6), 6.8 (3.8), and 8.6 (3.3) mg/l respectively. The drug had no effect on composite psychomotor and memory scores; nor was there alteration in any self assessment subscore. The mean drowsiness (P = 0.03) score was higher during treatment with 2400 mg GBP daily compared with matched placebo. Composite psychomotor (r = -0.47, P < 0.01), tiredness (r = 0.42, P < 0.01), and side effect (r = 0.61, P < 0.001) scores correlated significantly with seizure frequency but not with GBP dose. CONCLUSION: GBP is a well tolerated and effective antiepileptic drug which had no measurable effect on cognition but did produce sedation at the highest dose. This study also supports the suggestion that seizures can cause cognitive impairment.

Acetates↗
PubMed1997

Bile acid metabolism by colonic bacteria in continuous culture: effects of starch and pH.

Secondary bile acids (BA) have been shown to be involved as a promoting agent in the adenoma-carcinoma sequence of colorectal cancer. In previous studies, fermentation of starch has been shown to inhibit the degradation of primary to secondary BA by the colonic microflora. This study was designed to investigate BA metabolism in continuous cultures of mixed fecal bacteria to get further insights into the mechanisms of this inhibition. Fermentation vessels were fed with media containing cholic (0.6 g/l) and chenodeoxycholic acid (0.4 g/l). Cultures were either starch-free or enriched with starch (10 g/l). pH was controlled and adjusted to 7.0 or 6.0. Total culture duration was 28 days and concentrations of BA, short-chain fatty acids (SCFA), and starch were measured periodically. At pH 6, significantly more primary BA remained in the media and less secondary BA were produced. Total BA concentrations were lower at pH7. SCFA concentrations were higher in the vessels supplemented with starch. Starch was completely fermented and not present in significant amounts in any fermentation vial after the first week. These data indicate that bacterial breakdown of primary to secondary BA is inhibited when starch is simultaneously fermented. This effect can be explained by the reduction of pH resulting from SCFA production. Considering these findings, resistant starch which escapes assimilation in the small bowel may be a protective factor against colorectal cancer.

Acetates↗
PubMed1997

[Stomach volume reduction balloon for weight loss: what is the justification for this controversial method?].

UNLABELLED: Overweight and extreme morbid obesity are a common problem in our society. There are many therapeutic options currently available, but none of them can be considered as being ideal. One of these therapeutic interventions is the implantation of an intragastric balloon under endoscopic guidance. PURPOSE: Investigation of the effect of intragastric balloon Implantation on weight reduction. PATIENTS AND METHODS: In a prospective (and in part blinded) study 4 groups of patients (n = 10 each) were evaluated. In group I and II an intragastric balloon was implanted under endoscopic guidance. Group II had an intensive additional therapy by a dietition. Group I was advised to restrict themselves to a 1500 kcal diet. Group III did receive a sham implantation and the same additional therapy as group II. Group IV served as a control group and did not receive any type of treatment except the advice to restrict themselves to a diet. All balloons were explanted after 6 months. The overall follow-up rate was 18 months with a regular control of patients body weight. RESULTS: Patient inclusion criteria were comparable in all 4 groups. After 6 and 12 months a marked weight reduction was observed in group I and II when compared with group III and IV. This weight reduction was stable over time and reached statistical significance after 18 months. Additionally the results of group II (intensive additional therapy by a dietition) were better than in group I. Patients of group IV gained weight. No major complications due to the im- and explantation of the balloon were observed. CONCLUSIONS: The application of an intragastric balloon seems to be effective with regard of weight loss. The patient gets the chance to learn a more effective diet regimen which in our study population had a long lasting effect. Implantation of an intragastric balloon seems to be effective for a selective and highly motivated subpopulation of obese patients.

Adolescent↗
PubMed1996

Efficacy of moxidectin 0.5% pour-on against naturally acquired nematode infections in cattle.

The efficacy of 0.5% moxidectin pour-on at two dosages was evaluated in 30 cattle with naturally acquired gastrointestinal nematode infections. The cattle were ranked according to pretreatment fecal egg counts and body weights, and were randomly assigned from replicates to three treatment groups. The mean number of trichostrongyle eggs in pretreatment fecal samples did not differ among the groups. Groups I and II received 0.5% moxidectin pour-on at dosages of 0.25 mg moxidectin per kg body weight and 0.5 mg moxidectin per kg body weight, respectively, and Group III cattle received moxidectin-free vehicle (control cattle). The cattle were euthanized by complete replicate 14 or 15 days posttreatment for recovery of nematodes and examination of the pour-on sites. Treatment with moxidectin was associated with a significant reduction in fecal trichostrongyle egg counts compared with the control cattle; efficacy was 99.7% and > 99.9% for cattle in Groups I and II, respectively. Eleven species of adult nematodes (Haemonchus contortus, Haemonchus placei, Ostertagia ostertagi, Trichostrongylus axei, Trichostrongylus colubriformis, Bunostomum phlebotomum, Cooperia oncophora, Cooperia punctata, Nematodirus helvetianus, Oesophagostomum radiatum and Trichuris ovis) and 4th stage larvae of Ostertagia spp. and Trichostrongylus spp. were present in sufficient numbers in control cattle to evaluate the efficacy of moxidectin 0.5% pour-on. In all cases, treatment was associated with a significant reduction in the number of nematodes recovered at necropsy, with the efficacy of both dosages exceeding 99.9%. There were no significant differences in mean worm burdens or fecal egg counts between the two treated groups, and no adverse reactions were observed.

Abomasum↗
PubMed1996

On the mechanism of the post-activation depression of the H-reflex in human subjects.

It was demonstrated that the soleus H-reflex was depressed for more than 10 s following a preceding passive dorsiflexion of the ankle joint. This depression was caused by activation of large-diameter afferents with receptors located in the leg muscles, as an ischaemic block of large-diameter fibres just below the knee joint abolished the depression, whereas a similar block just proximal to the ankle joint was ineffective. The depression of the H-reflex was not caused by changes in motoneuronal excitability, as motor-evoked potentials by magnetic brain stimulation were not depressed by the same passive dorsiflexion. Therefore it was concluded that the long-lasting depression is due to mechanisms acting at presynaptic level. The transmission of the monosynaptic Ia excitation from the femoral nerve to soleus motoneurones was not depressed by the ankle dorsiflexion. The depression thus seems to be confined to those afferents that were activated by the conditioning dorsiflexion. In parallel experiments on decerebrate cats, more invasive methods have complemented the indirect techniques used in the experiments on human subjects. A similar long-lasting depression of triceps surae monosynaptic reflexes was evoked by a preceding conditioning stimulation of the triceps surae Ia afferents. This depression was accompanied by a reduction of the monosynaptic Ia excitatory postsynaptic potential recorded intracellularly in triceps surae motoneurones, but not by changes in the input resistance or membrane potential in the motoneurones. Stimulation of separate branches within the triceps surae nerve demonstrated that the depression is confined to those afferents that were activated by the conditioning stimulus. This long-lasting depression was not accompanied by a dorsal root potential. It is concluded that the long-lasting depression is probably caused by a presynaptic effect, but different from the "classical" GABAergic presynaptic inhibition which is widely distributed among afferent fibres and accompanied by dorsal root potentials. It is more probably related to the phenomenon of a reduced transmitter release from previously activated fibres, i.e. a homosynaptic post-activation depression. The consequences of this post-activation depression for the interpretation of results on spinal mechanisms during voluntary movements in man are discussed.

Adult↗
PubMed1996

Laparoscopic cholecystectomy for acute cholecystitis: is it really safe?

The prospectively collected data from 530 cholecystectomies performed in a university clinic from October 1989 to March 1991 were analyzed after 1 to 3 years of follow-up. The aim of this study was to compare the results of laparoscopic cholecystectomy (LC) for acute cholecystitis with that for routine symptomatic gallbladders. The preoperative, intraoperative, and postoperative parameters of 424 routine (noninflamed) LCs and 54 LCs for acutely inflamed gallbladders were compared under the "intention to treat" principle. Operating time was longer in the inflamed group (median 97 minutes versus 75 minutes; p < 0.0001). Significantly more adhesions (20% versus 8%), more blood loss (48% versus 19%), a higher incidence of bile spillage (28% versus 12%), and lost stones (19% versus 8%) were encountered in patients with acute cholecystitis. Common bile duct (CBD) injuries were also more frequent in that group (5.5% versus 0.2%; p = 0.005). The rate of conversion to open surgery was higher than with routine LCs (13% versus 4%). There were two deaths in the routine LC group and none in the acutely inflamed group. There was no difference in postoperative pain intensity or postoperative fatigue according to visual analog scale measurements. Patients with acute cholecystitis stayed only 1 day longer (median 4 days versus 3 days) in hospital. The quality of life scores indicate return to almost normal values by the 14th postoperative day. Long-term follow-up (1-3 years) did not reveal any delayed clinical adverse effects. In summary, LC for inflamed gallbladders has a higher conversion rate than LC for routine symptomatic gallbladders. If successfully performed, it has definite benefit for the patient in terms of better postoperative recovery. The trade-off is that the risk of CBD injury is significantly higher.

Acute Disease↗
PubMed1996

The role of protein kinase C in activation and termination of mitogen-activated protein kinase activity in angiotensin II-stimulated rat aortic smooth-muscle cells.

Mitogen-activated protein (MAP) kinases are a family of serine/threonine kinases activated by both tyrosine kinase and G-protein-linked receptor agonists. In rat aorta vascular smooth-muscle cells (VSMC), vasoconstrictors, angiotension II (AII), and alpha-thrombin (alpha-thr), as well as platelet-derived growth factor beta beta (PDGF) stimulated the tyrosine phosphorylation and activation of MAP kinase in a time- and concentration-dependent manner. Pre-treatment of cells with the protein kinase C (PKC) inhibitor Ro-318220, inhibited the initial increase in tyrosine phosphorylation of MAP kinase in response to vasoconstrictors, suggesting the involvement of PKC. Four isoforms of PKC were identified in VSMC by western blotting: alpha, beta, epsilon, and zeta. Downregulation of PKC alpha and PKC epsilon isoforms following chronic phorbol myristate 12, 13-acetate (PMA) pre-treatment resulted in the abolition of AII-stimulated MAP kinase activation. Selective downregulation of PKC alpha following pre-treatment with bryostatin 1 did not affect AII-stimulated MAP kinase. Preincubation of cells with Ro-318220 enhanced the activation of MAP kinase at later time points. In addition, Ro-318220 pre-treatment inhibited the induction by AII of a novel transcriptionally regulated phosphatase, MAP kinase phosphatase-1 (MKP-1). However, AII-mediated activation of MAP kinase was not prolonged by cycloheximide pre-treatment and was not maintained indefinitely by Ro-318220. These results demonstrate a specific role for the Ca(2+)-independent PKC isoform, PKC epsilon, in the activation of MAP kinase in response to vasoconstrictors, and suggest that PKC-mediated induction of MKP-1 plays no role in the termination of transiently activated MAP kinase.

Angiotensin II↗
PubMed1996

Quantitative comparison of excited state properties and intensity- dependent photosensitization by rose bengal.

A quantitative (multistep) excitation-deactivation model of rose bengal (RB) has been developed which includes energy and electron transfer to oxygen and the possibility of photoproduct formation via higher excited triplet-singlet states. The model is based on previous measurements of non-linear absorption (NLA) and emission of RB with picosecond pulses at 532 nm and on NLA measurements with nanosecond pulses. A coupled rate equation and photon transport equation approach for non-linear light-matter interaction is used. The resulting term scheme with all relevant excited state parameters confirms that (i) in the first excited state of RB, relevant absorption at 532 nm takes place only in the triplet, and (ii) the previously reported intensity dependence of RB-sensitized enzyme inhibition is well modelled by the intensity-dependent RB-T1 population and (as the main process) subsequent energy transfer to form singlet oxygen.

Lasers↗
PubMed1996

Effects of L-canavanine, an inhibitor of inducible nitric oxide synthase, on endotoxin mediated shock in rats.

The effects of L-canavanine, an inhibitor of nitric oxide synthase, on endotoxin-induced shock was investigated in the pentobarbitone anesthetized rat. Endotoxin infusion (2.5 mg kg-1 h-1 over 6 h) produced progressive and marked hypotension and hypoglycemia. Electron microscopy showed marked changes in the kidney, comprising severe endothelial cell disruption and the accumulation of platelets in the blood vessels. In the lung, there was marked accumulation of polymorphonuclear leukocytes in small blood vessels and endothelial disruption. Treatment with L-canavanine (10 mg kg-1 by bolus injection each hour starting 70 min after endotoxin or saline infusion) significantly reduced endotoxin-induced hypotension, without any effect on the hypoglycemia. This treatment markedly reduced the endotoxin-induced electron microscopical changes in the kidneys and lungs. Although L-canavanine, like L-NAME, inhibited both cerebellar constitute and splenic inducible nitric oxide synthase in vitro, in contrast to L-NAME it did not modify either arterial blood pressure or carotid artery blood flow in control rats. The data are consistent with L-canavanine being a selective inhibitor of inducible nitric oxide synthase, at least in vivo, and suggest that inhibitors of this enzyme may be beneficial in endotoxin-induced shock.

Animals↗