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Biomedical subjects

A Paul

Publications and source records attributed to A Paul.

At least 127 records · Page 7Linked to original sources
PubMed1998

Low-affinity nerve growth factor receptors (p75LNGFR) in human prostate tissue: stromal localisation.

Beta-nerve growth factor (beta-NGF) acts on high- and low-affinity receptors to effect sympathetic innervation. It is produced in the human prostate. This study aimed to demonstrate the presence of beta-NGF receptors and the distribution of p75LNGFR receptor protein in the human prostate. Radioligand binding assays were performed using microsomal preparations from benign prostatic hypertrophy (BPH) tissues but no specific binding of beta-NGF was demonstrated (n = 20). Furthermore, BPH and prostate cancer tissues were stained immunohistochemically for p75LNGFR. Immunohistochemistry localised p75LNGFR to tiny areas of prostate stroma postulated to be sympathetic nerves (BPH, n = 15; prostate adenocarcinoma, n = 15). Our results suggest that beta-NGF in the human prostate acts on stromal elements which, most likely, represent prostatic nerves. Beta-NGF may be an epithelial-stromal mediator of sympathetic nerve growth in the human prostate.

Adenocarcinoma↗
PubMed1998

Tumour necrosis factor stimulates stress-activated protein kinases and the inhibition of DNA synthesis in cultures of bovine aortic endothelial cells.

In this study, we examined the ability of tumour necrosis factor-alpha (TNF) to stimulate the mitogen-activated protein (MAP) kinase homologues p42/44 MAP kinase, c-Jun NH2-terminal kinase (JNK) and p38 MAP kinase and its effect upon DNA synthesis in primary cultures of bovine aortic endothelial cells (BAECs). TNF strongly stimulated p38 MAP kinase and JNK activity in both a time- and concentration-dependent manner. By contrast, TNF was a very poor activator of p42/44 MAP kinase relative to the known activator of p42/44 MAP kinase in endothelial cells, adenosine triphosphate (ATP). TNF-stimulated activation of p38 MAP kinase, and MAPKAP kinase-2, a known downstream target of p38 MAP kinase, was strongly inhibited by pre-incubation with the p38 MAP kinase inhibitor SB203580, whereas the minor activation of p42/44 MAP kinase was abolished by pre-incubation of the cell with the novel MAP kinase kinase 1 inhibitor PD098059. Addition of TNF resulted in a 50-60% decrease in DNA synthesis in BAECs. Pre-incubation with PD098059 or co-incubation with ATP failed to modify the inhibitory effect of TNF upon DNA synthesis. SB203580 reduced basal DNA synthesis by approximately 50%; however, if failed to modify the inhibition mediated by TNF. These results indicate that TNF strongly activates both p38 MAP kinase, JNK and, to a minor extent, p42/p44 MAP kinase. It is likely that only one of these kinases, JNK, plays a role in the regulation of DNA synthesis in these cells.

Animals↗
PubMed1998

Cognitive effects of anticonvulsant monotherapy in elderly patients: a placebo-controlled study.

Old age is recognized to be the commonest time in life to develop epilepsy. There is a perception that older patients are more sensitive to the deleterious cognitive effects of antiepileptic drugs (AEDs). Elderly patients (median age 70 years, range 60-88 years) taking anticonvulsant monotherapy (10 carbamazepine [CBZ], 8 sodium valproate [VPA], 5 phenytoin [PHT]) took an extra dose of their usual medication (200mg CBZ, 500mg VPA, 100mg PHT) and matched placebo each for a month in random order. The concentrations of AEDs were higher after 7 and 28 days of active treatment compared with placebo (7 days: CBZ 9.5 vs. 7.8 mg L(-1), p < 0.05; VPA 97 vs. 64 mg L(-1), p < 0.05; PHT 13 vs. 11 mg L(-1), p < 0.05; 28 days: CBZ 9.4 vs. 7.7 mg L(-1); p < 0.01, VPA 85 vs. 60 mg L(-1), p < 0.05; PHT 16 vs. 13 mg L(-1), p < 0.05). Despite these increases in concentration, there were no significant changes in attention, reaction time, finger tapping, memory, side-effect scale or sedation scoring during the active phases compared with placebo phases for the three drugs analysed together and separately. Elderly patients taking standard AEDs as monotherapy did not develop cognitive impairment when the dose was modestly increased within the target range for each drug.

Aged↗
PubMed1998

The Epilepsy Outcome Scale: the development of a measure for use with carers of people with epilepsy plus intellectual disability.

This paper describes the development of a new scale for the assessment of epilepsy in people with learning disabilities. The scale was developed and validated in consultation with principal carers, and reflects their concerns about seizures, their impact and their treatment. Further testing of the scale revealed high internal consistency, testretest reliability and a robust factor structure. The scale can be completed in 5-10 min and may be useful as an outcome measure both in clinical practice and in research trials.

Adaptation, Psychological↗
PubMed1998

Unacceptable results of the Mayo procedure for repair of abdominal incisional hernias.

OBJECTIVE: To evaluate the current practice of incisional hernia repair in Germany and analysis of the results of the Mayo duplication technique done in our hospital over a 10-year period. DESIGN: Nationwide survey, retrospective analysis. SETTING: University department, Germany. SUBJECTS: Survey of most surgical departments and of 114 patients with 135 incisional hernias in our unit. INTERVENTION: Mayo duplication repair incisional hernias. MAIN OUTCOME MEASURES: Common practice, recurrence rates, quality of life. RESULTS: The Mayo overlap is the preferred technique in most surgical departments. The estimated failure rates (12% or less) in general practice are grossly underestimated. In our hospital the recurrence rate after Mayo duplication repair was 61/114 (54%) during a follow up time of 5.7 years with a follow-up-rate of 84%. Univariate and multivariate analyses failed to identify any predisposing factors. All patients with incisional hernias had limitations their physical function. CONCLUSIONS: The widely used Mayo procedure leads to unacceptable results for repair of incisional hernias and other techniques should be evaluated and used more often. Repair of an incisional hernia does not improve overall quality of life.

Female↗
PubMed1998

Hypoxic stimulation of the stress-activated protein kinases in pulmonary artery fibroblasts.

Pulmonary hypertension in response to chronic hypoxia is invariably accompanied by remodeling of the pulmonary vessels but the mechanism by which hypoxia increases the replication of vascular cells is unknown. To investigate the hypothesis that hypoxia stimulates intracellular kinase cascades we measured the activity of "classic" mitogen-activated protein (MAP) kinase pathways and "stress- activated" MAP kinase pathways in bovine pulmonary artery fibroblasts subjected to hypoxia for up to 30 h. Hypoxia (1% O2) stimulated strongly the stress-activated protein kinases, c-Jun NH2-terminal kinase (JNK) and p38 MAP kinase. Two peaks of p38 MAP kinase activity at 6 and 24 h were associated with an increase in the activity of mitogen-activated protein kinase-activated protein (MAPKAP) kinase-2, the immediate downstream target of p38 MAP kinase. Furthermore, the second phase of p38 MAP kinase activity could be reversed if cells were reoxygenated after 12 h. These data suggest that hypoxic stimulation of pulmonary artery cells is mediated by activation of the stress-activated protein kinases.

Animals↗
PubMed1998

Sleep studies of adults with severe or profound mental retardation and epilepsy.

Sleep patterns of people with mental retardation have received little research attention. This is an important gap in knowledge because understanding the relation between sleep and wakefulness may be critical to care provision. Descriptive sleep information on 28 people with severe or profound mental retardation and epilepsy was presented here. Sleep EEG data, studied both conventionally and by means of a neural network-based sleep analysis system suggest atypical sleep stages with significant depletion of REM sleep and a predominance of "indiscriminate" non-REM sleep. Sleep diaries completed by caregivers reveal lengthy sleep period times, especially among those with profound mental retardation. Possible explanations for these results and their implications were discussed.

Adolescent↗
PubMed1998

[Revitalizing donor livers after cardiovascular arrest with venous oxygen persufflation].

The experimental study investigates the resuscitation of livers procured from non heart beating donors by venous systemic oxygen persufflation in a pig transplantation model. In group 1 livers were harvested from donor animals after 60 min of potassium induced cardiac arrest. Livers were then flushed and preserved in 4 degrees C cold University of Wisconsin solution for 4 hrs. Then liver transplantation was performed in recipient animals. Animals of group 2 received the same treatment, but during hypothermic storage we applied venous systemic oxygen gas persufflation (VSOP) via the supra-hepatic vena cava. Livers of group 3 were harvested without warm ischemia and without oxygen treatment during cold ischemic storage and were then transplanted. All recipient animals of group 2 and 3 survived the five day follow-up time. All recipient animals of group 1 died a few hours after liver reperfusion due to circulatory shock or liver failure. The liver quality of group 2 recipient animals was similar to group 3 livers, because serum transaminase levels and blood coagulation test showed no significantly different values between those groups. Our data suggest that livers procured from non heart beating donors after 1 hr of cardiac arrest can be resuscitated and successfully transplanted by therapeutic treatment with VSOP.

Animals↗
PubMed1998

Infant nutrition and cognitive development in the first offspring of a national UK birth cohort.

Several studies show a modest beneficial effect of breastfeeding on cognitive development after controlling for sociodemographic confounders. It is still unclear, however, to what extent this is due to the nutritional advantage of breast milk or to environmental influences associated with breastfeeding. We compared verbal ability scores at age 8 years in 511 first-born offspring of the National Survey of Health and Development who were ever or never breastfed, adjusting for paternal occupation, maternal education, maternal cognitive performance, attendance at nursery school, and maternal age at birth of the participant. A positive association between breastfeeding and cognitive performance was found but this was no longer the case after adjusting for either paternal occupation, maternal education, or maternal cognitive performance in turn. In contrast, an association between breastfeeding and cognitive function was not found for mothers of these offspring. Breastfeeding was increasingly associated with a non-manual social class across the generations although it remains unclear how this might mediate the effect of breastfeeding on cognitive performance.

Adult↗
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

Learning disability and epilepsy. 2, a review of available outcome measures and position statement on development priorities.

People with epilepsy plus learning disabilities pose a challenge in terms of clinical management and research investigation, and, to date, the measurement of outcomes in this population has been limited. There have been uncertainties concerning both the 'what' and the 'how' of assessment. This paper presents a comprehensive review of available outcome measures across nine domains, i.e. relating to seizures, drugs, cognitive function, behaviour, social functioning, carer functioning, attitudes, motivation and 'quality of life'. This last domain reflects more global measures designed to encompass several assessment strands. The uses and limitations of each scale is discussed and, where data are available, psychometric properties are also presented. The paper concludes with suggestions for the further development of outcome measures in this population.

Epilepsy↗
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↗