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Biomedical subjects

R J Walker

Publications and source records attributed to R J Walker.

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

A long-term comparison between enalapril and captopril on insulin sensitivity in normotensive non-insulin dependent diabetic volunteers.

BACKGROUND: There are conflicting reports about the effects of angiotensin converting enzyme inhibitors on insulin sensitivity and glycaemic control. In addition, the chronic effects of ACEI on insulin sensitivity in normotensive but insulin resistant individuals have been controversial. AIM: To determine the long-term effects of low-dose captopril or enalapril on insulin sensitivity and lipid parameters in normotensive non-insulin dependent diabetic volunteers. METHODS: Twenty-eight normotensive non-insulin dependent diabetes mellitus subjects on diet alone or diet plus oral hypoglycaemic agents were randomized in a single-blind cross-over study to receive either captopril (12.5 mg daily) or enalapril (5 mg daily). Initially, captopril was compared with enalapril for 28 days with a 28-day washout period between drug regimens. For the long-term study, the subjects then remained on the second ACEI for a further 11 months. Insulin sensitivity was measured using the isoglycaemic hyperinsulinaemic clamp (insulin infusion rate 20 mIU/kg/min) at the start and completion of each part of the cross-over study and then at 3, 6 and 12 months of drug therapy. Fasting glucose, insulin, HbA1, lipids and lipoproteins were measured at the start of each clamp. RESULTS: No first or second order carry-over effects were demonstrated between the ACEIs. No differences were detected between enalapril and captopril on insulin sensitivity at any of the time points. Statistically significant hypotension was avoided, and at doses used the ACEIs did not modify any parameters of glycaemic control over the 12-month study period. There were no significant alterations in plasma cholesterol, triglycerides, HDL cholesterol or Apo A1 levels during the study. CONCLUSIONS: Long-term low-dose ACEIs (captopril/enalapril) do not modify insulin sensitivity, glycaemic control or lipids in normotensive non-insulin dependent diabetic subjects.

Aged↗
PubMed1997

Effect of treatment with simvastatin on serum cholesteryl ester transfer in patients on dialysis. PERFECT Study Collaborative Group.

BACKGROUND: Plasma cholesteryl ester transfer activity is increased in patients with chronic renal failure on dialysis who have elevated levels of apolipoprotein B (apoB)-containing lipoproteins. Simvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitor, reduces levels of these lipoproteins but the effect of treatment on cholesteryl ester transfer activity in patients on dialysis remains to be determined. METHODS: We measured serum newly synthesized cholesteryl ester transfer (NCET) activity, lecithin:cholesterol acyltransferase (LCAT) activity and serum lipid, lipoprotein and apolipoprotein concentrations before and immediately after 6 months treatment with simvastatin (10 mg daily, n = 24) or placebo (n = 29) in 53 patients with chronic renal failure receiving haemodialysis or continuous ambulatory peritoneal dialysis (CAPD). RESULTS: Simvastatin therapy significantly reduced serum cholesterol, LDL cholesterol, apoB concentrations, and both NCET (P = 0.001) and LCAT (P = 0.012) rates. The decrease in NCET activity was correlated significantly with the corresponding decrease in apoB concentration (r = 0.715, P < 0.001) and LCAT activity (r = 0.715, P < 0.001) during simvastatin therapy and was no longer significant when apoB concentration (P = 0.14) or LCAT activity (P = 0.07) were controlled. CONCLUSIONS: These data show that simvastatin therapy reduces serum NCET rates, and suggest that this may be linked to the concomitant decrease in levels of apoB-containing lipoproteins which are acceptors of transferred cholesteryl esters, and to the decrease in serum LCAT rates in patients with chronic renal failure with treatment.

Adolescent↗
PubMed1997

The impact of anticipatory grief on caregivers of persons with Alzheimer's disease.

Caregivers of persons with Alzheimer's disease (AD) and other dementias are known to experience many physical and emotional problems. However, research has consistently shown that the relationship between the demands of caregiving and the effects on the caregiver is not strong. Despite considerable research, a full understanding of how the demands of caregiving uniquely impact the individual has not been established. The present study examines anticipatory grief, an emotion that has not been studied to date for its possible impact on the current functioning of caregivers. Structured interviews, consisting primarily on standardized measures, were conducted with 100 caregivers. Results of the study show that physical and emotional problems and the expectation to place the patient out of the home were more likely to occur among those caregivers who expressed the most intense grief and those feelings of remorse and anger characteristic of the anger and guilt stages of grief.

Adult↗
PubMed1996

Direct and modulatory effects of FMRFamide, SKPYMRFamide and acety1-SKPYMRFamide on LPa2, LPa3, and RPa3 identified neurons of Helix lucorum.

Three neuroactive peptides with an RFamide carboxyl terminal, one a tetrapeptide, FMRFamide, and two heptapeptides, SKPYMRFamide and acetyl-SKPYMRFamide, evoke direct and modulatory effects on identified neurons from left (LPa2, LPa3) and right (RPa3) parietal ganglia of the land snail. Helix lucorum. Local application of tetrapeptide and heptapeptides induce hyperpolarization or outward current when neurons are clamped at the resting potential. The reversal potential of these direct responses is near the potassium equilibrium potential. All investigated FMRFamide-related peptides reduce reversibly the inward current to local acetylcholine (ACh) application onto the neuron soma. Threshold concentrations of peptides for an inhibitory action on ACh-induced current are 0.5-1.0 microM, ID50 = 0.7-1.2 microM, SKPYMRFamide evokes parallel shift to right of ACh dose-response curves increasing the ED50 for ACh but without changing the Hill number. SKPYMRFamide does not change the reversal potential of the ACh-induced inward current. It was concluded that SKPYMRFamide reduces the affinity of ACh for ACh receptor without a change in the number of ligand-binding sites per ACh receptor molecule. FMRFamide-related peptides can reduce the affinity of ACh for cholinergic receptors through inhibition of the molecular mechanism connecting the ACh receptor with its ion channels.

Acetylcholine↗
PubMed1996

Biphasic actions of the benzodiazepine receptor inverse agonist RU34347 in the rat cerebellar slice.

We have characterised the biphasic response of the benzodiazepine receptor inverse agonist RU34347 in the rat cerebellar slice preparation using extracellular electrophysiological recordings from Purkinje cells. RU34347 (10 fM-10 nM) produced an increase in GABA(A)-mediated inhibition at between 10 fM and 10 nM, a response normally associated with benzodiazepine agonists. This response was biphasic, being dose dependent between 10 fM and the peak effect at 10 pM, and inversely related to concentration between 100 pM and 10 nM. Associated with this increase in inhibition was a decrease in firing rate, also showing a biphasic concentration-response relationship. The agonist-like response was composed of two elements, an initial increase occurring after 5 min followed by a slow decline over the next 20 min. This second, declining, phase was more evident at higher concentrations of RU34347. The peak effect seen at 10 pM was fully antagonised by 1 microM flumazenil, a benzodiazepine receptor antagonist. This concentration of flumazenil also antagonised the decrease in firing rate induced by 10 pM RU34347. The response to 10 nM RU34347 was further characterised since the largest second phase decline was demonstrated at this concentration. 10 nM flumazenil fully antagonised the second, declining, phase of the response, but not the magnitude of the initial increase. A partial antagonism of the peak effect was seen with 1 microM flumazenil, and a full antagonism at 10 microM flumazenil. This effect was similar to that observed with Ro15-4513 in a previous study. Therefore, we investigated the binding of RU34347 to diazepam-insensitive benzodiazepine receptors. [3H]Ro15-4513 was displaced by Ro15-4513, flumazenil and Ro19-4603, but not by RU34347. Therefore, although the electrophysiological data correlate well with that previously reported for Ro15-4513, RU34347 does not displace Ro15-4513 binding at the diazepam-insensitive benzodiazepine receptor. Therefore, either both ligands bind to complimentary sites on the same receptor complex, or both induce a similar physiological response through an action on different receptors.

Animals↗
PubMed1996

Reduction of cerebellar GABAA responses by interleukin-1 (IL-1) through an indomethacin insensitive mechanism.

Recently, a role of IL-1 in the central nervous system has been described, principally a fever-inducing effect in the hypothalamus through a prostaglandin second messenger system. IL-1 has also been shown to potentiate gamma-aminobutyric acid (GABAA) responses in embryonic chick neurones. This study describes the investigation of the effect of IL-1 on GABAA responses within the in vitro rat cerebellar slice, a preparation containing intact neuronal circuitry. Stimulation of the area of passage of paralleled fibres produced a pure GABAA inhibition of the spontaneous firing of Purkinje cells. 5 and 10 ng/ml IL-1 produced a reduction in the duration of inhibition 10 min after beginning perfusion of IL-1. This effect reversed within 15 min of washing out the IL-1. 10 ng/ml IL-1 also reduced the effects of exogenously-applied GABA (0.1 mM) with the same time course. In the presence of 1 uM indomethacin, there was no change in the effect of the IL-1. It can therefore be concluded that the reduction in cerebellar GABAA responses by IL-1 is not mediated by the indomethacin-sensitive prostaglandin second messenger system.

Animals↗
PubMed1996

Nematode neuropeptides: Localization, isolation and functions.

Historically, peptidergic substances (in the form of neurosecretions) were linked to moulting in nematodes. More recently, there has been a renewal of interest in nematode neurobiology, initially triggered by studies demonstrating the localization of peptide immunoreactivities to the nervous system. Here, David Brownlee, Ian Fairweather, Lindy Holden-Dye and Robert Walker will review progress on the isolation of nematode neuropeptides and efforts to unravel their physiological actions and inactivation mechanisms. Future avenues for research are suggested and the potential exploitation of peptidergic pathways in future therapeutic strategies highlighted.

Journal Article↗
PubMed1996

NADPH diaphorase activity in peptidergic neurones of the parasitic nematode, Ascaris suum.

The histochemical marker for nitric oxide synthase, NADPH diaphorase, is known to co-localize in mammalian neurones with various classical neurotransmitters and neuropeptides. The nervous system of the parasitic nematode Ascaris suum has previously been shown to contain both NADPH diaphorase activity and neuropeptide immunoreactivity. This study examined the possibility that NADPH diaphorase and neuropeptide immunoreactivity may co-exist in the same neurones. Two antisera were used, one raised to KYSALMFamide, a C-terminal synthetic analogue of SALMFamide 1 (GFNSALMFamide), and another that recognizes calcitonin-gene-related peptide (CGRP). We provide evidence that in a distinct subset of neurones in the ventral, dorsal and lateral ganglia NADPH diaphorase staining and SALMFamide-like immunoreactivity are co-localized, suggesting a possible role for nitric oxide in modulating neuropeptide activity in these regions. CGRP-like immunoreactivity was less widely distributed, and was not consistently co-localized with NADPH diaphorase.

Animals↗
PubMed1996

Evolution and overview of classical transmitter molecules and their receptors.

All the classical transmitter ligand molecules evolved at least 1000 million years ago. With the possible exception of the Porifera and coelenterates (Cnidaria), they occur in all the remaining phyla. All transmitters have evolved the ability to activate a range of ion channels, resulting in excitation, inhibition and biphasic or multiphasic responses. All transmitters can be synthesised in all three basic types of neurones, i.e. sensory, interneurone and motoneurone. However their relative importance as sensory, interneurone or motor transmitters varies widely between the phyla. It is likely that all neurones contain more than one type of releasable molecule, often a combination of a classical transmitter and a neuroactive peptide. Second messengers, i.e. G proteins and phospholipase C systems, appeared early in evolution and occur in all phyla that have been investigated. Although the evidence is incomplete, it is likely that all the classical transmitter receptor subtypes identified in mammals, also occur throughout the phyla. The invertebrate receptors so far cloned show some interesting homologies both between those from different invertebrate phyla and with mammalian receptors. This indicates that many of the basic receptor subtypes, including benzodiazepine subunits, evolved at an early period, probably at least 800 million years ago. Overall, the evidence stresses the similarity between the major phyla rather than their differences, supporting a common origin from primitive helminth stock.

Acetylcholine↗
PubMed1996

Novel azole derivatives are antagonists at the inhibitory GABA receptor on the somatic muscle cells of the parasitic nematode Ascaris suum.

The somatic muscle cells of the parasitic nematode Ascaris suum possess GABA receptors that gate chloride conductances in a similar fashion to the mammalian GABAA receptor subtype. These receptors mediate muscle relaxation and are the site of action of the anthelmintic piperazine. The properties of this receptor differ from the properties of the GABA-gated chloride receptors in the mammalian host, in particular they are not as sensitive to mammalian GABA receptor antagonists such as bicuculline and picrotoxin. Using two-electrode intracellular electrophysiological recording techniques from Ascaris muscle cells, we have tested the potency of a series of azole derivatives for their ability to block the chloride-dependent GABA response. The lead compound, SN606078, 2-(2,6-dichloro-4-trifluoromethylphenyl)-4-(4,5-dicyano-1H-imidazo l-2-yl)-2H- 1,2,3-triazole, and 4 structurally related compounds reversibly blocked the conductance increase elicited by 30 microM GABA with IC50s of less than 10 microM. SN606078 (10 microM) decreased the slope of the dose-response curve for GABA, suggesting a non-competitive mechanism of action. In two-electrode voltage clamp experiments, 10 microM SN606078 blocked the outward current elicited by 20 microM GABA in a voltage-dependent manner with 72 +/- 2% inhibition at -20 mV and 49 +/- 6% inhibition at -40 mV. These observations indicate that SN606078 may act as an open-channel blocker of the GABA-gated chloride channel in A. suum.

Animals↗
PubMed1996

Anticipatory grief and AIDS: strategies for intervening with caregivers.

Anticipatory grief may have beneficial effects for caregivers of people with HIV infection or AIDS. However, the duration of the illness and the stigmatization and multiple losses associated with the disease may impede the caregiver's ability to effectively engage in the grief process. This article discusses the impact of these aspects of the disease on the anticipatory grief process and mourning tasks for caregivers at each stage of the illness. Intervention strategies developed to help the caregiver remain actively involved with the patient and simultaneously grieve losses and prepare for death are specified.

Acquired Immunodeficiency Syndrome↗
PubMed1996

Depression or grief? The experience of caregivers of people with dementia.

The exploratory study discussed in this article attempted to shed some light on the nature of the depression and grief experienced by caregivers of people with dementia. The findings suggest that the depression so frequently described in the literature may not be as severe or clinically significant as previously thought and that it may be more precisely described as anticipatory grief. Viewing caregivers apparent depression as being the result of grief over the losses they are experiencing may assist practitioners in planning and evaluating the effectiveness of clinical interventions specifically designed for this growing group of clients.

Adult↗
PubMed1996

A psychoeducational group intervention for family members of persons with HIV/AIDS.

We describe a psychoeducational group intervention for family members of persons living with AIDS. The 33 family members were compared with 13 waiting-list controls in order to evaluate the effectiveness of the intervention. We focus on the practice aspects of the intervention, its development and implementation, and our belief that it is an apparently effective approach for helping family members work through the social and emotional aspects of the devastating impact of HIV/AIDS.

Adaptation, Psychological↗
PubMed1996

The effect of oral vanadyl sulfate on body composition and performance in weight-training athletes.

The effects of oral vanadyl sulfate (VOSO4) (0.5 mg/kg/day) on anthropometry, body composition, and performance were investigated in a 12-week, double-blind, placebo-controlled trial involving weight-training volunteers. Performance was assessed in the treatment (VS) and placebo (P) groups using 1 and 10 repetitions maximum (RM) for the bench press and leg extension. Thirty-one subjects completed the trial, with 2 VS subjects withdrawing because of apparent side effects. There were no significant treatment effects for anthropometric parameters and body composition during the trial. Both groups had significant improvements in performance but the only significant effect of treatment was a Treatment x Time interaction in the 1 RM leg extension (p = .002), which could have arisen because the VS group had a lower performance at baseline in this test. It was concluded that oral vanadyl sulfate was ineffective in changing body composition in weight-training athletes, and any modest performance-enhancing effect requires further investigation.

Absorptiometry, Photon↗
PubMed1996

Altered cellular biosynthesis in human peritoneal mesothelial cells exposed to dialysis solutions.

Peritoneal dialysis (PD) solutions can produce changes in the peritoneal membrane and structure which are related to the high glucose concentrations and low pH of these solutions. This study was designed to examine the effects of high glucose (76-214 mM) and low pH (5.3) solutions on human peritoneal mesothelial cells in culture. Changes in mesothelial cell biosynthesis and cell numbers were evident within 2 hours of exposure to unmodified dialysis solutions. In the development of new dialysis solutions, human peritoneal mesothelial cells in culture provide a good in vitro model to determine potential toxicity.

Animals↗
PubMed1995

Structure-activity studies of RFamide analogues on central neurones of Helix aspersa.

The effects of FMRFamide were compared with those of FMRFamide analogues, FLRFamide, LFRFamide, FFRFamide, LLRFamide, D-FMRFamide, F-D-MRFamide and FM-D-RFamide, and the fragments, MRFamide and LRFamide, on identified central neurones, F1, F2, F5 and E16, of the snail Helix aspersa, using intracellular recording and two electrode voltage clamp techniques. All FMRFamide analogues showed an inhibitory effect on F1 neurones with an order of potency: FLRFamide > FMRFamide > FFRFamide > LFRFamide >> LLRFamide. FMRFamide and FLRFamide exhibited a biphasic response on F2 neurones. At lower concentrations (< 10 microM), both peptides usually only excited while at higher concentrations (> 30 microM), exhibited an excitation followed by an inhibition. FFRFamide only excited F2 while LFRFamide and LLRFamide only inhibited F2. LRFamide and MRFamide (100 microM) were inactive on both F1 and F2. FLRFamide, LFRFamide, LLRFamide, FFRFamide and D-FMRFamide showed cross-interaction on the outward current induced by FMRFamide in F5. All peptides induced an outward current and also reduced the FMRFamide-induced current reversibly. In contrast, MRFamide, LRFamide and F-D-MRFamide failed to have direct effects on these neurones nor interact with the FMRFamide-induced current. We conclude that on F2 neurones Phe is essential for the activation of the RFamide receptor mediating the excitation and Met or Leu are important to activate the RFamide receptors mediating the inhibition. Removal of the N-terminal Phe, to give LRFamide and MRFamide render the peptides inactive. Therefore a tetrapeptide sequence is essential for the biological activity of FMRFamide analogues on these Helix neurones. FLRFamide, LFRFamide, LLRFamide, FFRFamide and D-FMRFamide exhibit a cross-interaction with FMRFamide. It is possible that these peptides also act on the same class of RFamide receptors as agonists to cause cross desensitization.

Animals↗