Management of hypertension. Ideal body weight is not realistic goal for lifestyle intervention.
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Blood Pressure↗
Biomedical subjects
G Williams
Publications and source records attributed to G Williams.
A novel family of cyclic peptide antagonists suggests that N-cadherin specificity is determined by amino acids that flank the HAV motif.
The classical cadherins (e.g. N-, E-, and P- cadherin) are well established homophilic adhesion molecules; however, the mechanism that governs cadherin specificity remains contentious. The classical cadherins contain an evolutionarily conserved His-Ala-Val (HAV) sequence, and linear peptides harboring this motif are capable of inhibiting a variety of cadherin-dependent processes. We now demonstrate that short cyclic HAV peptides can inhibit N-cadherin function. Interestingly, the nature of the amino acids that flank the HAV motif determine both the activity and specificity of the peptides. For example, when the HAV motif is flanked by a single aspartic acid, which mimics the natural HAVD sequence of N-cadherin, the peptide becomes a much more effective inhibitor of N-cadherin function. In contrast, when the HAV motif is flanked by a single serine, which mimics the natural HAVS sequence of E-cadherin, it loses its ability to inhibit the N-cadherin response. Our results demonstrate that subtle changes in the amino acids that flank the HAV motif can account for cadherin specificity and that small cyclic peptides can inhibit cadherin function. An emerging role for cadherins in a number of pathological processes suggests that the cyclic peptides reported in this study might be developed as therapeutic agents.
3T3 Cells↗
INP, a novel N-cadherin antagonist targeted to the amino acids that flank the HAV motif.
The classical cadherins are homophilic binding molecules that play fundamental roles in several biological processes, including axonal growth and synaptic plasticity. The structures of the amino-terminal homophilic binding domains of N-cadherin and E-cadherin have been resolved. However, the mechanisms that govern cadherin binding and specificity remain contentious. In the present study we have used a peptide competition approach to probe for small linear determinants of cadherin binding. We demonstrate that a linear peptide mimetic of a short sequence in ECD1 of N-cadherin (INPISGQ) functions as a highly specific and potent antagonist of N-cadherin function with an IC(50) value of approximately 15 microM. Peptide mimetics of the corresponding motif in chick R-cadherin also inhibited N-cadherin function, albeit with lower efficacy. In contrast, peptide mimetics of the corresponding motif in E- or P-cadherin failed to inhibit N-cadherin function. A short cyclic peptide that contained only the INP motif from N-cadherin was also a potent N-cadherin antagonist (IC(50) approximately 15 microM). Analysis of existing crystal structures suggests that the peptides are likely to antagonize N-cadherin function by binding to the region that flanks the HAV motif at the adhesion dimer interface.
3T3 Cells↗
CAMs and axonal growth: a critical evaluation of the role of calcium and the MAPK cascade.
Calcium has long been recognized as a key player in the control of axonal growth and guidance. Recent studies lend support to this pivotal role by showing that local changes in calcium can directly induce the formation of filopodia in vivo and turn a growth cone in vitro. Under normal growth conditions, the L1 adhesion molecule has now been shown to induce local rather than global changes in calcium in growth cones, and this suggests that cell adhesion molecules (CAMs) use localized calcium transients to stimulate axonal growth and guidance. A number of recent reports have demonstrated that the neurite outgrowth response stimulated by L1 and other adhesion molecules (NCAM, N-cadherin, laminin) also depends in part upon the integrity of the MAPK cascade in cells. In this review we consider the recent data and suggest that calcium and the MAPK cascade might be required for very distinct growth cone functions. Finally, we will consider the contentious issue of how the above CAMs activate signaling cascades in growth cones and review the recently available data that support the hypothesis that at least one of these CAMs (N-cadherin) might promote growth cone motility by directly interacting with the FGFR in growth cones.
Animals↗
Pseudomembranous enteritis after proctocolectomy: report of a case.
Intestinal pseudomembrane formation, sometimes a manifestation of antibiotic-associated diarrheal illnesses, is typically limited to the colon but rarely may affect the small bowel. A 56-year-old female taking antibiotics, who had undergone proctocolectomy for idiopathic inflammatory bowel disease, presented with septic shock and hypotension. A partial small-bowel resection revealed extensive mucosal pseudomembranes, which were cultured positive for Clostridium difficile. Intestinal drainage contents from an ileostomy were enzyme immunoassay positive for C. difficile toxin A. Gross and histopathologic features of the small-bowel resection specimen were similar to those characteristic of pseudomembranous colitis. The patient was treated successfully with metronidazole. These findings suggest a reservoir for C. difficile also exists in the small intestine and that conditions for enhanced mucosal susceptibility to C. difficile overgrowth may occur in the small-bowel environment of antibiotic-treated patients after colectomy. Pseudomembranous enteritis should be a consideration in those patients who present with purulent ostomy drainage, abdominal pain, fever, leukocytosis, or symptoms of septic shock.
Abdominal Pain↗
The role of medial hypothalamic serotonin in the suppression of feeding in a rat model of colitis.
BACKGROUND & AIMS: Experimental colitis is associated with anorexia that is attenuated by treatment with an interleukin (IL)-1 receptor antagonist. Serotonin (5-hydroxytryptamine [5-HT]) is a potent inhibitor of feeding, and its release from the hypothalamus is stimulated by IL-1. We have tested the hypotheses that anorexia associated with experimental colitis results from increased activity of hypothalamic 5-HT neurons and that the increase in activity occurs secondary to an increase in availability of tryptophan, the precursor of 5-HT. METHODS: In vivo 5-HT release and regional hypothalamic 5-HT and tryptophan concentrations were measured in rats with 2,4,6,-trinitrobenzene sulfonic acid (TNBS)-induced colitis, healthy controls, and animals pair-fed to match the food intake of the colitic group. Food intake in the colitic group was assessed after depletion of brain 5-HT by p-chlorophenylalanine (PCPA). RESULTS: In the colitic group, release of 5-HT from the hypothalamic paraventricular nucleus (PVN) was 3-fold (P = 0.01) and 14-fold (P < 0.001) higher than in control and pair-fed groups, respectively. Concentrations of tryptophan were similar in each group in all hypothalamic regions. Food intake was significantly increased in the colitic group after PCPA treatment but was not restored to control values. CONCLUSIONS: In animals with TNBS-induced colitis, 5-HT release from the PVN is increased. The increase in food intake after depletion of brain 5-HT suggests that hypothalamic 5-HT contributes to anorexia but is not the only mediator. Increased 5-HT release in the colitic group was not driven by increased precursor availability.
Amino Acids↗
Pulmonary function after modified venovenous ultrafiltration in infants: a prospective, randomized trial.
OBJECTIVE: We sought to examine the effects of modified venovenous ultrafiltration after cardiopulmonary bypass on pulmonary compliance in infants. METHODS: We prospectively enrolled 38 infants undergoing their first operation for congenital heart disease. Infants were randomized to receive 20 minutes of modified ultrafiltration after bypass or control. Static and dynamic compliance was measured after induction of anesthesia, before and immediately after filtration in the operating theater, 1 hour after return to the pediatric intensive care unit, and 24 hours after the operation. Length of time on the ventilator, inotropic requirements, and length of stay in the intensive care unit were recorded. RESULTS: Modified ultrafiltration produced a significant immediate improvement in dynamic (pre-ultrafiltration 2.5 +/- 1.9 mL/cm H(2)O to post-ultrafiltration 2.9 +/- 2.7 mL/cm H(2)O, P =.03) and static (pre-ultrafiltration 2.1 +/- 0.9 mL/cm H(2)O to post-ultrafiltration 2.9 +/- 2.1 mL/cm H(2)O, P =.04) compliance. However, there was no significant difference in the change in dynamic (P =.3) or static (P =.7) compliance in the ultrafiltration and control groups when compared before the operation, after the operation, and at 24 hours. There was no significant difference in the time to extubation between patients and control subjects (140 +/- 91 hours vs 90 +/- 58 hours) or the length of intensive care unit stay (10.0 +/- 9.1 days vs 7.4 +/- 5.7 days). CONCLUSIONS: Modified ultrafiltration produces an improvement in pulmonary compliance after bypass in infants. However, these improvements are not sustained past the immediate post-ultrafiltration period and do not lead to a decreased length of intubation or intensive care unit stay.
Cardiopulmonary Bypass↗
Regulation of neuropeptide Y release from hypothalamic slices by melanocortin-4 agonists and leptin.
We have examined the regulation of the orexigenic neurotransmitter, NPY, in hypothalamic slices of rat brain to discover whether the leptin or melanocortin receptor-4 (MCR-4) agonists, which act as satiety signals, can influence the release of this neurotransmitter. Basal and potassium-stimulated NPY release from hypothalamic slices was not significantly altered by the addition of recombinant murine leptin. However, the melanocortin-4 agonists, alpha-MSH and MT-II, significantly inhibited potassium-stimulated NPY release (p < 0.01) without significantly altering basal NPY release. However, the MCR-4 antagonist, agouti-related protein, did not significantly alter either basal or stimulated NPY release. In conclusion, hypothalamic NPY release can be attenuated by MCR-4 agonists, but not by leptin, suggesting that the activation of MCR-4 receptors leading to satiety can also further inhibit food intake through an inhibition of orexigenic NPYergic activity.
Agouti-Related Protein↗
Effect of cytokines on hypothalamic neuropeptide Y release in vitro.
Studies involving altered energy balance states in rodents have demonstrated that hypothalamic neuropeptide Y (NPY) activity is strongly activated in states of negative energy balance, such as periods of dietary restriction or starvation. However, in cancer cachexia, when there is a significant reduction in body weight as a result of appetite loss, leading to loss in fat and lean tissue mass, there is no augmentation in the activity of the hypothalamic NPY system. Therefore, we have examined whether cytokines, interleukin (IL)-1, IL-1beta, IL-6, and tumor-necrosis factor-alpha (TNF-alpha; cachectin), which are elevated in cancer patients, can attenuate NPY release from hypothalamic slices in vitro. None of the cytokines altered either the basal or stimulated NPY release from the hypothalamic slices. However, we were able to measure a significant reduction in potassium-stimulated NPY release (-60%) by using the nonselective voltage-dependent calcium channel blocker NiCl (30 microM) without any effect on basal release, as a positive control. Therefore, we suggest that the failure to activate the hypothalamic NPY system in states of cancer cachexia cannot be attributed to a cytokine-induced reduction in neurotransmitter release.
Animals↗
Toxicological evaluation of New Zealand deer velvet powder. Part I: acute and subchronic oral toxicity studies in rats.
Potential toxic effects of acute and subchronic dosage regimens of deer velvet powder have been assessed in rats following OECD guidelines. In the acute study, rats of both sexes were exposed to a single dose of 2 g/kg body weight. There was no mortality or other signs of toxicity during 14 days' observation. Furthermore, no significant alteration either in relative organ weights or their histology was discernible at terminal autopsy. In the 90-day subchronic study, deer velvet was administered in 1 g/kg daily doses by gavage to rats. A control group of rats received water only. There was no effect on body weight, food consumption, clinical signs, haematology and most parameters of blood chemistry including carbohydrate metabolism, liver and kidney function. No significant differences were seen between the mean organ weights of the adrenal, kidney and brain in rats treated with deer velvet and control rats. However, there was a significant difference (P<0.05) in the group mean relative liver weight (3.52 +/- 0.30 vs 3.81 +/- 0.26 g/100 g body weight) of deer velvet-treated and control male rats. The gross necropsy and pathological examination of rats treated with deer velvet did not reveal any abnormalities in tissue morphology. Based on these results, it may be concluded that rats had no deer velvet treatment-related toxicological and histopathological abnormalities at the doses administered, despite the observed minor changes in liver weight.
Administration, Oral↗
Aspergillosis presenting as Koebner's phenomenon in a healed scald.
Koebner's phenomenon is an uncommon postburn complication. The following report describes a female child who sustained an 80% total body surface area scald which healed with conservative treatment. She developed a cutaneous Aspergillus infection involving only the previously scalded areas. The uninjured skin remained normal. She went on to develop systemic aspergillosis and died of multi-organ failure.
Aspergillosis↗
Application of enhanced dynamic wedge to stereotactic radiotherapy.
Stereotactic radiotherapy has developed into a useful treatment technique in which conformal dose distributions can be delivered with precision and accuracy. In some cases, the position of the target volume relative to surrounding critical structures demands careful evaluation of fixed beam paths so that dose to these critical structures can be minimized. Micromultileaf collimators aid in conforming dose to the target volume but may not allow adjustment of an individual beam's intensity (intensity modulation) in an effort to achieve dose uniformity throughout the treatment volume. Enhanced dynamic wedge (EDW) is demonstrated to be a valuable tool in improving the dose distribution in stereotactic radiotherapy treatments in which these fixed, conformal fields must be used due to constraints in beam trajectories. Four cases are presented which show the potential for gain in dose uniformity with the addition of EDW. These cases represent typical applications of EDW to conformal stereotactic radiotherapy.
Humans↗
Electronic telephone directory listings: preferred sampling frame for a population-based study of childhood cancer in Australia.
PURPOSE: We report our telephone-based system for selecting community control series appropriate for a complete Australia-wide series of Ewing's sarcoma cases. METHODS: We used electronic directory random sampling to select age-matched controls. The sampling has all listed telephone numbers on an up-dated CD-Rom. RESULTS: 95% of 2245 telephone numbers selected were successfully contacted. The mean number of attempts needed was 1.94, 58% answering at the first attempt. On average, we needed 4.5 contacts per control selected. Calls were more likely to be successful (reach a respondent) when made in the evening (except Saturdays). The overall response rate among contacted telephone numbers was 92.8%. Participation rates among female and male respondents were practically the same. The exclusion of unlisted numbers (13.5% of connected households) and unconnected households (3.7%) led to potential selection bias. However, restricting the case series to listed cases only, plus having external information on the direction of potential bias allow meaningful interpretation of our data. CONCLUSION: Sampling from an electronic directory is convenient, economical and simple, and gives a very good yield of eligible subjects compared to other methods.
Adolescent↗
The hypothalamus and the regulation of energy homeostasis: lifting the lid on a black box.
The hypothalamus is the focus of many peripheral signals and neural pathways that control energy homeostasis and body weight. Emphasis has moved away from anatomical concepts of 'feeding' and 'satiety' centres to the specific neurotransmitters that modulate feeding behaviour and energy expenditure. We have chosen three examples to illustrate the physiological roles of hypothalamic neurotransmitters and their potential as targets for the development of new drugs to treat obesity and other nutritional disorders. Neuropeptide Y (NPY) is expressed by neurones of the hypothalamic arcuate nucleus (ARC) that project to important appetite-regulating nuclei, including the paraventricular nucleus (PVN). NPY injected into the PVN is the most potent central appetite stimulant known, and also inhibits thermogenesis; repeated administration rapidly induces obesity. The ARC NPY neurones are stimulated by starvation, probably mediated by falls in circulating leptin and insulin (which both inhibit these neurones), and contribute to the increased hunger in this and other conditions of energy deficit. They therefore act homeostatically to correct negative energy balance. ARC NPY neurones also mediate hyperphagia and obesity in the ob/ob and db/db mice and fa/fa rat, in which leptin inhibition is lost through mutations affecting leptin or its receptor. Antagonists of the Y5 receptor (currently thought to be the NPY 'feeding' receptor) have anti-obesity effects. Melanocortin-4 receptors (MC4-R) are expressed in various hypothalamic regions, including the ventromedial nucleus and ARC. Activation of MC4-R by agonists such as alpha-melanocyte-stimulating hormone (a cleavage product of pro-opiomelanocortin which is expressed in ARC neurones) inhibits feeding and causes weight loss. Conversely, MC4-R antagonists such as 'agouti' protein and agouti gene-related peptide (AGRP) stimulate feeding and cause obesity. Ectopic expression of agouti in the hypothalamus leads to obesity in the AVY mouse, while AGRP is co-expressed by NPY neurones in the ARC. Synthetic MC4-R agonists may ultimately find use as anti-obesity drugs in human subjects Orexins-A and -B, derived from prepro-orexin, are expressed in specific neurones of the lateral hypothalamic area (LHA). Orexin-A injected centrally stimulates eating and prepro-orexin mRNA is up regulated by fasting and hypoglycaemia. The LHA is important in receiving sensory signals from the gut and liver, and in sensing glucose, and orexin neurones may be involved in stimulating feeding in response to falls in plasma glucose.
Animals↗
One-year treatment of obesity: a randomized, double-blind, placebo-controlled, multicentre study of orlistat, a gastrointestinal lipase inhibitor.
OBJECTIVE: To assess the efficacy and tolerability of orlistat (Xenical) in producing and maintaining weight loss over a 12-month period. DESIGN: Patients were randomized to double-blind treatment with either orlistat 120 mg or placebo three times daily, in conjunction with a low-energy diet, for 12 months. SETTING: Five centres in the UK. SUBJECTS: 228 obese adult patients with body mass index between 30 and 43 kg/m2 and mean weight 97 kg (range 74-144 kg). INTERVENTIONS: All patients were prescribed a low-energy diet, providing 30% of energy from fat, designed to produce an individually tailored energy deficit of approximately 600 kcal/day, for a run-in period of 4 weeks and then 12 months, plus orlistat 120 mg or placebo three times daily. MAIN OUTCOME MEASURES: Change in body weight (the primary efficacy parameter), waist circumference and adverse events were reviewed regularly, together with serum lipids, insulin, glucose and plasma levels of fat-soluble vitamins and beta carotene. RESULTS: Based on an intent-to-treat analysis, after 1 y of treatment patients receiving orlistat had lost an average of 8.5% of their initial body weight compared with 5.4% for placebo-treated patients; 35% of the orlistat group lost at least 5% of body weight compared with 21% of the placebo group (P < 0.05), and 28% and 17%, respectively (P = 0.04) lost at least 10% of body weight. Orlistat-treated patients showed significant decreases (P < 0.05) in serum levels of total cholesterol, low density lipoprotein cholesterol, and in the low density lipoprotein: high density lipoprotein ratio in comparison with placebo. Both groups had similar adverse-event profiles, except for gastrointestinal events, which were 26% more frequent in the orlistat group but were mostly mild and transient. To maintain normal plasma levels of fat-soluble vitamins, supplements of vitamins A, D and E were given to 1.8%, 8.0% and 3.6%, respectively, of orlistat-treated patients, compared with 0.9% of placebo-treated patients for each vitamin type. After 1 y, the decrease in vitamin E and beta carotene was significantly greater in orlistat-treated patients compared with those receiving placebo (P < 0.001). No significant change was found in the mean vitamin E:total cholesterol ratio in either group after 52 weeks. CONCLUSIONS: Orlistat, in conjunction with a low-energy diet, produced greater and more frequent significant weight loss than placebo during 1 y of treatment. One-third of orlistat-treated patients achieved clinically relevant weight loss (> or = 5% initial body weight). There was also an improvement in relevant serum lipid parameters. Fat-soluble vitamin supplements may be required during chronic therapy. Orlistat was well tolerated and offers a promising new approach to the long-term management of obesity.
Adult↗
Potential of intermittent hormone therapy for M+ and M0 prostate cancer patients.
Increasingly animal and clinical studies suggest that intermittent therapy may improve the duration of hormone dependence in patients with prostate cancer. However there remains uncertainty as to optimal duration of treatment and level of prostate-specific antigen (PSA) before treatment is restarted. The aim of this study was to identify risk factors that predict duration of therapy in prostate cancer patients receiving intermittent hormone therapy. Any patients who had achieved PSA complete remission after hormone therapy for metastatic or locally advanced prostate cancer were included in the study. Fifty patients entered on intermittent hormone therapy after achieving a PSA complete remission. In all, 57% of patients remained off treatment at 12 months and the median time for restarting further hormone therapy was 14 months. At 1 y, 95% of patients retreated are progression free and overall 92% are alive at 3 y. There was some evidence that there was a slower progression to require treatment in older M0 patients and those who had been on treatment for more than 9 months. Although M0 patients receiving radiation concurrently after initial hormone down staging had a slower recurrence rate, 53% of M0 patients treated with hormone alone remained off hormones for more than one year. Clearly selection cannot be excluded as a cause for this good survival. However as overall survival in this study is at least as good as that of patients with M0 disease on hormone therapy in the immediate arm of the MRC immediate vs deferred therapy study, there is a case to extend examination of this approach to a randomized trial. This might also include patients failing to achieve PSA complete remission in order to examine the issue of whether continued androgen withdrawal is required in the terminal treatment phase of hormone-resistant patients to keep the hormone sensitive clone under control. Prostate Cancer and Prostatic Diseases (2000) 3, 286-289
Journal Article↗
Central Australian Nurse Management Model (CAN Model): a strategic approach to the recruitment and retention of remote-area nurses.
This paper introduces a new strategic approach, the Central Australian Nurse Management Model (CAN Model), to manage remote area nursing services. Central Australia is home to approximately 45,000 people, of whom 30% are Aborigines with a health status that is markedly lower than the rest of the population. While the Federal, State and Territory governments have policies in place to address health inequities, improvement has been hindered by the difficulty in recruiting and retaining suitable nursing staff in remote areas. Implementation of the three key initiatives that comprise the CAN Model has succeeded in attracting, stabilising and skilling a remote area nursing workforce, fundamental to achieving better health outcomes in Aboriginal populations.
Health Policy↗
Other assessments: prostate size and prostate specific antigen.
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Biomarkers, Tumor↗