SIRT1 is increased in affected brain regions and hypothalamic metabolic pathways are altered in Huntington disease.

AIMS: Metabolic dysfunction is involved in modulating the disease process in Huntington disease (HD) but the underlying mechanisms are not known. The aim of this study was to investigate if the metabolic regulators sirtuins are affected in HD. METHODS: Quantitative real-time polymerase chain reactions were used to assess levels of SIRT1-3 and downstream targets in post mortem brain tissue from HD patients and control cases as well as after selective hypothalamic expression of mutant huntingtin (HTT) using recombinant adeno-associated viral vectors in mice. RESULTS: We show that mRNA levels of the metabolic regulator SIRT1 are increased in the striatum and the cerebral cortex but not in the less affected cerebellum in post mortem HD brains. Levels of SIRT2 are only increased in the striatum and SIRT3 is not affected in HD. Interestingly, mRNA levels of SIRT1 are selectively increased in the lateral hypothalamic area (LHA) and ventromedial hypothalamus (VMH) in HD. Further analyses of the LHA and VMH confirmed pathological changes in these regions including effects on SIRT1 downstream targets and reduced mRNA levels of orexin (hypocretin), prodynorphin and melanin-concentrating hormone (MCH) in the LHA and of brain-derived neurotrophic factor (BDNF) in the VMH. Analyses after selective hypothalamic expression of mutant HTT suggest that effects on BDNF, orexin, dynorphin and MCH are early and direct, whereas changes in SIRT1 require more widespread expression of mutant HTT. CONCLUSIONS: We show that SIRT1 expression is increased in HD-affected brain regions and that metabolic pathways are altered in the HD hypothalamus.

Hyperbaric Oxygen as an Adjunctive Therapy Postfasciotomy for Unilateral Supraspinatus Rhabdomyolysis and Compartment Syndrome.

We present a case of severe supraspinatus muscle rhabdomyolysis following overexertion in a young male. Preexisting risk factors included illicit drug use. Even single muscle rhabdomyolysis can cause significant renal failure, and in our case the use of intravenous flushing was used in conjunction with hyperbaric oxygen after muscle compartment fasciotomy to maximize muscle recovery and renal protection in a manual worker (musician). Clinicians should be alert to severe muscle pain requiring narcotics after strenuous use.

The impact of the healthcare system in Barbados (provision of health insurance and the benefit service scheme) on the use of herbal remedies by Christian churchgoers.

AIM: To determine the impact of health insurance and the government's Benefit Service Scheme, a system that provides free drugs to treat mostly chronic illnesses to persons aged 16 to 65 years, on the use of herbal remedies by Christian churchgoers in Barbados. METHODS: The eleven parishes of Barbados were sampled over a six-week period using a survey instrument developed and tested over a four-week period prior to administration. Persons were asked to participate and after written informed consent, they were interviewed by the research team. The data were analysed by the use of IBM SPSS version 19. The data were all nominal, so descriptive statistics including counts, the frequencies, odds ratios and percentages were calculated. RESULTS: More than half of the participants (59.2%) were female, a little less than a third (29.9%) were male, and one tenth of the participants (10.9%) did not indicate their gender The majority of the participants were between the ages of 41 and 70 years, with the age range of 51-60 years comprising 26.1% of the sample interviewed. Almost all of the participants were born in Barbados (92.5%). Approximately 33% of the respondents indicated that they used herbal remedies to treat various ailments including chronic conditions. The odds ratio of persons using herbal remedies and having health insurance to persons not using herbal remedies and having health insurance is 1.01 (95% CI 0.621, 1.632). There was an increase in the numbers of respondents using herbal remedies as age increased. This trend continued until the age group 71-80 years which showed a reduction in the use of herbal remedies, 32.6% of respondents compared with 38.3% of respondents in the 61-70-year category. CONCLUSIONS: The data demonstrated that only a third of the study population is using herbal remedies for ailments. Health insurance was not an indicator neither did it influence the use of herbal remedies by respondents. The use of herbal remedies may not be associated with affluence. The reduction in the use of herbal remedies in the age group 71-80 years could be due to primarily a lower response rate from this age group, and secondarily due to the Benefit Service Scheme offering free medication to persons who have passed the age of 65 years.

The impact of the healthcare system in Barbados (Provision of health insurance and the Benefit Service Scheme) on the use of herbal remedies by Christian churchgoers / El Impacto del sistema de salud en Barbados (Provisión de seguro de salud y Plan de Servicios y Beneficios) sobre el uso de remedios herbarios por parte de los feligreses Cristianos

AIM: To determine the impact of health insurance and the government's Benefit Service Scheme, a system that provides free drugs to treat mostly chronic illnesses to persons aged 16 to 65 years, on the use of herbal remedies by Christian churchgoers in Barbados. METHODS: The eleven parishes of Barbados were sampled over a six-week period using a survey instrument developed and tested over a four-week period prior to administration. Persons were asked to participate and after written informed consent, they were interviewed by the research team. The data were analysed by the use of IBM SPSS version 19. The data were all nominal, so descriptive statistics including counts, the frequencies, odds ratios and percentages were calculated. RESULTS: More than half of the participants (59.2%) were female, a little less than a third (29.9%) were male, and one tenth of the participants (10.9%) did not indicate their gender. The majority of the participants were between the ages of 41 and 70 years, with the age range of 51-60 years comprising 26.1% of the sample interviewed. Almost all of the participants were born in Barbados (92.5%). Approximately 33% of the respondents indicated that they used herbal remedies to treat various ailments including chronic conditions. The odds ratio of persons using herbal remedies and having health insurance to persons not using herbal remedies and having health insurance is 1.01 (95% CI 0.621, 1.632). There was an increase in the numbers of respondents using herbal remedies as age increased. This trend continued until the age group 71-80 years which showed a reduction in the use of herbal remedies, 32.6% of respondents compared with 38.3% of respondents in the 61-70-year category. CONCLUSIONS: The data demonstrated that only a third of the study population is using herbal remedies for ailments. Health insurance was not an indicator neither did it influence the use of herbal remedies by respondents. The use of herbal remedies may not be associated with affluence. The reduction in the use of herbal remedies in the age group 71-80 years could be due to primarily a lower response rate from this age group, and secondarily due to the Benefit Service Scheme offering free medication to persons who have passed the age of 65 years.

OBJETIVO: Investigar si el Seguro de Saludy el Plan de Servicios y Beneficios del Gobierno - un sistema que proporciona medicina libremente para tratar principalmente enfermedades crónicas en personas de 16 a 65 anos de edad - influyen en el uso de remedios herbarios por los feligreses cristianos en Barbados. MÉTODOS: Se realizó un muestreo en once provincias de Barbados por un período de seis semanas, usando como instrumento una encuesta desarrollada y probada durante un período de cuatro semanas antes de ser aplicada. Se le pidió participación a distintas personas y luego de obtener el consen-timiento informado por escrito, las mismas fueron entrevistadas por el equipo de investigación. Los datos fueron analizados mediante la versión 19 de IBM SPSS. Todos los datos eran nominales, de modo que se calcularon las estadísticas descriptivas, incluyendo conteos, frecuencia, cociente de probabilidades (odds ratio), y porcentajes. RESULTADOS: Más de la mitad de los participantes (59.2%) eran mujeres; poco menos de un tercio (29.9%) eran hombres; y una décima parte de los participantes (10.9%) no indicó su sexo. La mayoría de los participantes se encontraban entre las edades de 41 y 70 anos, para un rango de edad de 51-60 anos que comprendía el 26.1% de la muestra entrevistada. Casi todos los participantes nacieron en Barbados (92.5%). Aproximadamente 33% de los entrevistados indicaron que usaban remedios herbarios para tratar varias dolencias, incluyendo condiciones crónicas. El odds ratio de las personas que usan remedios herbarios y poseen seguro de salud es 1.01 (95% CI 0.621, 1.632). Seprodujo un aumento en el número de entrevistados que usaban remedios herbarios, según aumentaba su edad. Esta tendencia continuó hasta el grupo etario de 71-80 anos, el cual mostró una reducción en el uso de remedios herbarios, 32.6% de los entrevistados en comparación con el 38.3% de los entrevistados en la categoría de los 61-70 anos. CONCLUSIONS: Los datos mostraron que sólo una tercera parte de la población está usando remedios herbarios para sus dolencias. El seguro de salud no fue un indicador ni influyó sobre el uso de remedios herbarios por los entrevistados. El uso de remedios herbarios no puede asociarse con la afluencia. La reducción en el uso de remedios herbarios en el grupo etario 71-80 anos podrían deberse principalmente a una tasa de respuesta más baja de este grupo etario, y secundariamente al Plan de Servicios y Beneficios que ofrece medicamentos gratuitamente a personas que han pasado la edad de 65 anos.

Fixation and deformity correction by plate osteosynthesis of a tibial shaft malunion after traditional African bone setting.

Given the global nature of modern travel and the possibility of deployment to the African continent, it is conceivable that medical officers in the course of their general duties may be exposed to patients managed with traditional bone setting techniques. Whilst these techniques may prove effective for many, complications may still arise and their management may be challenging.

Capecitabine combined with oxaliplatin (CapOx) in clinical practice: how significant is peripheral neuropathy?

BACKGROUND: There is speculation that peripheral neuropathy (PN) with capecitabine and oxaliplatin (CapOx; 130 mg/m(2), day 1, every 21 days) may be more common than with FOLFOX4 (5-fluorouracil and oxaliplatin 85 mg/m(2), day 1, every 14 days). We aimed to determine PN incidence and associations during CapOx, and 6 and 12 months after CapOx. PATIENTS AND METHODS: Retrospective audit of 188 oxaliplatin-naive colorectal cancer patients (87 adjuvant, 101 palliative) who received at least one cycle of CapOx. Neurosensory Common Toxicity Criteria Adverse Events version 3 were applied. RESULTS: Overall, 94% experienced acute PN. Worst severities for adjuvant and palliative patients, respectively, were grade 1, 44% and 54%; grade 2, 35% and 32%; grade 3, 16% and 3%; grade 4, 0% and 1% and grade unclear 1% and 1%. Two patients developed PN after CapOx completion despite no symptoms during treatment. Chronic PN at 6 months affected 57% and 18% of adjuvant and palliative patients, respectively. At 12 months, 35% and 16% were affected. Chronic PN at 12 months was associated with cumulative oxaliplatin dose but not age, gender, acute myotonia, pseudolaryngospasm or grade 2 or more PN during treatment. CONCLUSION: Incidence of acute PN during CapOx appears similar to FOLFOX4 but chronic PN in adjuvant patients may be more common with CapOx.

Preclinical safety testing of DISC-hGMCSF to support phase I clinical trials in cancer patients.

BACKGROUND: DISC-hGMCSF is a gH-deleted HSV-2 based vector expressing human GM-CSF that is being developed for cancer immunotherapy. To support first clinical use, a range of preclinical safety studies were performed using DISC-hGMCSF in addition to DISC-murine-GMCSF and the backbone vector, TA-HSV. METHODS: The toxicity of the DISC vectors was assessed by repeated dose, neurovirulence and neuroinvasiveness studies in mice, and by safety studies in rabbits, guinea pigs and athymic nude mice. Studies were also conducted to determine whether the vector could establish latency in local ganglia in mice following intradermal injection, and whether it could reactivate from the latent state. The vector biodistribution following intravenous administration was also investigated in mice, using PCR to detect vector DNA. RESULTS: The DISC vectors were essentially non-toxic in all the systems studied. No adverse reactions were seen in mice receiving four intravenous doses of DISC-mGMCSF and the results from studies of neurovirulence, neuroinvasiveness, local tolerance in rabbit, general safety in mice and guinea pigs and safety in athymic nude mice were consistent with DISC being unable to replicate and cause disease. The vector could establish latency in local ganglia in mice, but at low efficiency, and could not reactivate infectious virions. Following intravenous administration, vector DNA was widely distributed up to Day 28, but by Day 56 had disappeared from gonads and brain and was only found in blood and liver. CONCLUSION: The panel of safety studies provided evidence that DISC-hGMCSF will be unable to replicate and cause disease, and has low toxicity in man. These data were presented to the Medicines Control Agency and the Gene Therapy Advisory Committee as part of the regulatory submissions for a clinical trial in melanoma patients. These submissions have been approved, and DISC-hGMCSF has now entered a phase I clinical trial in the UK by direct intratumoural injection.

Chelation and intercalation: complementary properties in a compound for the treatment of Alzheimer's disease.

Selective application of metal chelators to homogenates of human Alzheimer's disease (AD) brain has led us to propose that the architecture of aggregated beta-amyloid peptide, whether in the form of plaques or soluble oligomers, is determined at least in part by high-affinity binding of transition metals, especially copper and zinc. Of the two metals, copper is implicated in reactive oxygen species generating reactions, while zinc appears to be associated with conformational and antioxidant activity. We tested the copper chelators trientine, penicillamine, and bathophenanthroline for their ability to mobilize brain Abeta as measured against our benchmark compound bathocuproine (BC). All of these agents were effective in solubilizing brain Abeta, although BC was the most consistent across the range of AD brain tissue samples tested. Similarly, all of the copper chelators depleted copper in the high-speed supernatants. BC alone had no significant effect upon zinc levels in the soluble fraction. BC extraction of brain tissue from C100 transgenic mice (which express human Abeta but do not develop amyloid) revealed SDS-resistant dimers as Abeta was mobilized from the sedimentable to the soluble fraction. NMR analysis showed that, in addition to its copper chelating properties, BC interacts with Abeta to form a complex independent of the presence of copper. Such hybrid copper chelating and "chain breaking" properties may form the basis of a rational design for a therapy for Alzheimer's disease.

Preclinical evaluation of "whole" cell vaccines for prophylaxis and therapy using a disabled infectious single cycle-herpes simplex virus vector to transduce cytokine genes.

The development of genetically modified "whole" tumor cell vaccines for cancer therapy relies on the efficient transduction and expression of genes by vectors. In the present study, we have used a disabled infectious single cycle-herpes simplex virus 2 (DISC-HSV-2) vector constructed to express cytokine or marker genes upon infection. DISC-HSV-2 is able to infect a wide range of tumor cells and efficiently express the beta-galactosidase reporter gene, granulocyte-macrophage colony-stimulating factor (GM-CSF), or IL-2 genes. Gene expression occurred rapidly after infection of tumor cells, and the level of production of the gene product (beta-galactosidase, GM-CSF, or IL-2) was shown to be both time-and dose-dependent. Vaccination with irradiated DISC-mGM-CSF or DISC-hIL-2-infected murine tumor cells resulted in greatly enhanced immunity to tumor challenge with live parental tumor cells compared with control vaccines. When used therapeutically to treat existing tumors, vaccination with irradiated DISC-mGM-CSF-infected tumor cells significantly reduced the incidence and growth rates of tumors when administered locally adjacent to the tumor site, providing up to 90% protection. The prophylactic and therapeutic efficacy of DISC-mGM-CSF-infected cells was shown initially using a murine renal cell carcinoma model (RENCA), and the results were confirmed in two additional murine tumor models: the M3 melanoma and 302R sarcoma. Therapy with DISC-infected RENCA "whole" cell vaccines failed to reduce the incidence or growth of tumor in congenitally T-cell deficient (Nu+/Nu+) mice or mice depleted of CD4+ and/or CD8+ T-lymphocytes, confirming that both T-helper and T-cytotoxic effector arms of the immune response are required to promote tumor rejection. These preclinical results suggest that this "novel" DISC-HSV vector may prove to be efficacious in developing genetically modified whole-cell vaccines for clinical use.

Soluble pool of Abeta amyloid as a determinant of severity of neurodegeneration in Alzheimer's disease.

Genetic evidence strongly supports the view that Abeta amyloid production is central to the cause of Alzheimer's disease. The kinetics, compartmentation, and form of Abeta and its temporal relation to the neurodegenerative process remain uncertain. The levels of soluble and insoluble Abeta were determined by using western blot techniques, and the findings were assessed in relation to indices of severity of disease. The mean level of soluble Abeta is increased threefold in Alzheimer's disease and correlates highly with markers of disease severity. In contrast, the level of insoluble Abeta (also a measure of total amyloid load) is found only to discriminate Alzheimer's disease from controls, and does not correlate with disease severity or numbers of amyloid plaques. These findings support the concept of several interacting pools of Abeta, that is, a large relatively static insoluble pool that is derived from a constantly turning over smaller soluble pool. The latter may exist in both intracellular and extracellular compartments, and contain the basic forms of Abeta that cause neurodegeneration. Reducing the levels of these soluble Abeta species by threefold to levels found in normal controls might prove to be a goal of future therapeutic intervention.

Low glycogen and branched-chain amino acid ingestion do not impair anaplerosis during exercise in humans.

We examined the hypothesis that increasing the rate of branched-chain amino acid (BCAA) oxidation, during conditions of low glycogen availability, reduces the level of muscle tricarboxylic acid cycle intermediates (TCAI) by placing a carbon "drain" on the cycle at the level of 2-oxoglutarate. Six men cycled at approximately 70% of maximal oxygen uptake for 15 min under two conditions: 1) low preexercise muscle glycogen (placebo) and 2) low glycogen combined with BCAA ingestion. We have previously shown that BCAA ingestion increased the activity of branched-chain oxoacid dehydrogenase, the rate-limiting enzyme for BCAA oxidation in muscle, compared with low glycogen alone [M. L. Jackman, M. J. Gibala, E. Hultman, and T. E. Graham. Am. J. Physiol. 272 (Endocrinol. Metab. 35): E233-E238, 1997]. Muscle glycogen concentration was 185 +/- 22 and 206 +/- 22 mmol/kg dry wt at rest for the placebo and BCAA-supplemented trials, respectively, and decreased to 109 +/- 18 and 96 +/- 10 mmol/kg dry wt after exercise. The net increase in the total concentration of six measured TCAI ( approximately 95% of TCAI pool) during exercise was not different between trials (3.97 +/- 0. 34 vs. 3.88 +/- 0.34 mmol/kg dry wt for the placebo and BCAA trials, respectively). Muscle 2-oxoglutarate concentration decreased from approximately 0.05 at rest to approximately 0.03 mmol/kg dry wt after exercise in both trials. The magnitude of TCAI pool expansion in both trials was similar to that seen previously in subjects who performed an identical exercise bout after a normal mixed diet [M. J. Gibala, M. A. Tarnopolsky, and T. E. Graham. Am. J. Physiol. 272 (Endocrinol. Metab. 35): E239-E244, 1997]. These data suggest that increasing the rate of BCAA oxidation has no measurable effect on muscle TCAI during exercise with low glycogen in humans. Moreover, it appears that low resting glycogen per se does not impair the increase in TCAI during moderate exercise.

Molecular isoform distribution and glycosylation of acetylcholinesterase are altered in brain and cerebrospinal fluid of patients with Alzheimer's disease.

The glycosylation of acetylcholinesterase (AChE) in CSF was analyzed by lectin binding. AChE from Alzheimer's disease (AD) patients was found to bind differently to two lectins, concanavalin A and wheat germ agglutinin, than AChE from controls. As multiple isoforms of AChE are present in both CSF and brain, we examined whether the abnormal glycosylation of AD AChE was due to changes in a specific molecular isoform. Globular amphiphilic dimeric (G2a) and monomeric (G1a) isoforms of AChE were found to be differentially glycosylated in AD CSF. Glycosylation of AChE was also altered in AD frontal cortex but not in cerebellum and was also associated with an increase in the proportion of light (G2 and G1) isoforms. This study demonstrates that the glycosylation of AChE is altered in the AD brain and that changes in AChE glycosylation in AD CSF may reflect changes in the distribution of brain isoforms. The study also suggests that glycosylation of AChE may be a useful diagnostic marker for AD.

Idiopathic hypothalamic dysfunction with dilated unresponsive pupils: report of two cases.

Idiopathic hypothalamic dysfunction is a rare but well-defined entity in childhood characterized by adipsia-hypernatremia, obesity, poor thermoregulation, and disturbance of pituitary function. Two cases of idiopathic hypothalamic dysfunction are described. There are 10 previously reported cases in the literature, and the clinical features are compared. The present cases are unique in that the patients also had bilaterally dilated unresponsive pupils. In the first case, there was no demonstrable pathology at autopsy; in the second case, lymphocytic infiltration of the hypothalamus and midbrain associated with neuronal loss was present at autopsy. Possible etiologies are discussed.

Depletion of hypothalamic growth hormone-releasing hormone by neonatal monosodium glutamate treatment reveals an inhibitory effect of betamethasone on growth hormone secretion in adult rats.

Rats were treated with monosodium glutamate (MSG), 4 mg/g on alternate days for the first 10 days of life, to induce lesions of the arcuate nucleus and destroy the majority of growth hormone-releasing hormone (GHRH) neurones. At 10 weeks of age, control (n = 42) and MSG-treated (n = 36) male rats were used to test the effect of glucocorticoids on growth hormone (GH) secretion. Each treatment group was divided into six study groups to determine the effect of betamethasone (BM), administered either 3 or 20 h prior to sacrifice, alone and in combination with hypoglycaemia (insulin 0.1 U/100 g). BM treatment of male rats was without effect on plasma GH levels in control animals. In contrast, glucocorticoid administered either 3 h before sacrifice or the previous evening significantly reduced circulating GH (p less than 0.001) in MSG-treated animals. The difference in plasma GH response to BM pretreatment in control rats and those with lesions of the arcuate nucleus indicates a hypothalamic action of glucocorticoids, presumably on somatostatin and GHRH neurones. In control animals the effects appear to be counterbalancing, but following destruction of GHRH neurones an uncompensated inhibitory influence was observed. Male MSG-treated rats had lower body weight (-25%) and reduced hypothalamic GHRH (-89%) and pituitary GH content (-69%) compared to male controls. Female rats which had undergone the same neonatal MSG treatment (n = 40) when sacrificed 1 week after their male counterparts showed similar reductions in body weight (-15%), hypothalamic GHRH (-74%), and pituitary GH (-67%).(ABSTRACT TRUNCATED AT 250 WORDS)