A ventromedullary relay involved in the hypothalamic and chemoreceptor activation of sympathetic postganglionic neurones to skeletal muscle, kidney and splanchnic area

Electrical stimulation of hypothalamic and midbrain defence area sites eliciting a cholinergic vasodilatation in the hindlimb activates vasodilator fibres supplying skeletal muscle. Simultaneous baroreceptor mediated suppression of sympathetic vasoconstrictor activity to the muscle and postfiring depression of vasoconstrictor activity contribute to the development of the vasodilatation during and after the stimulus. The observation of a differential pattern of activation of muscle and renal vasoconstrictor fibres implies a reciprocal influence exerted on these sympathetic outflows by neurones in the defence areas of the brain.     

Expression of genes encoding innate host defense molecules in normal human monocytes in response to Candida albicans

Little is known about the regulation and coordinated expression of genes involved in the innate host response to Candida albicans. We therefore examined the kinetic profile of gene expression of innate host defense molecules in normal human monocytes infected with C. albicans using microarray technology. Freshly isolated peripheral blood monocytes from five healthy donors were incubated with C. albicans for 0 to 18 h in parallel with time-matched uninfected control cells. RNA from monocytes was extracted and amplified for microarray analysis, using a 42,421-gene cDNA chip. Expression of genes encoding proinflammatory cytokines, including tumor necrosis factor alpha, interleukin 1 (IL-1), IL-6, and leukemia inhibitory factor, was markedly enhanced during the first 6 h and coincided with an increase in phagocytosis. Expression of these genes returned to near baseline by 18 h. Genes encoding chemokines, including IL-8; macrophage inflammatory proteins 1, 3, and 4; and monocyte chemoattractant protein 1, also were strongly up-regulated, with peak expression at 4 to 6 h, as were genes encoding chemokine receptors CCR1, CCR5, CCR7, and CXCR5. Expression of genes whose products may protect monocyte viability, such as BCL2-related protein, metallothioneins, CD71, and SOCS3, was up-regulated at 4 to 6 h and remained elevated throughout the 18-h time course. On the other hand, expression of genes encoding T-cell-regulatory molecules (e.g., IL-12, gamma interferon, and transforming growth factor beta) was not significantly affected during the 18-h incubation. Moreover, genes encoding IL-15, the IL-13 receptor (IL-13Ra1), and CD14 were suppressed during the 18-h exposure to C. albicans. Thus, C. albicans is a potent inducer of a dynamic cascade of expression of genes whose products are related to the recruitment, activation, and protection of neutrophils and monocytes.     

Uptake blockade of endocannabinoids in the NTS modulates baroreflex-evoked sympathoinhibition

Previous studies supporting a possible physiological role for an endogenous cannabinoid, arachidonylethanolamide (AEA, anandamide), showed a significant increase in AEA content in the nucleus tractus solitarius (NTS) after an increase in blood pressure (BP) and prolonged baroreflex inhibition of renal sympathetic nerve activity (RSNA) after exogenous AEA microinjections into the NTS. These results, along with other studies, support the hypothesis that endogenous AEA can modulate the baroreflex through cannabinoid CB(1) receptor activation within the NTS. This study was performed to characterize the physiological role of endogenously released cannabinoids (endocannabinoids) in regulating baroreflex control of RSNA through actions in the NTS. Endocannabinoid effects were assessed by measuring the RSNA baroreflex response to increased pressure after bilateral microinjections of AM404, an endocannabinoid transport inhibitor, into the NTS of adult male Sprague Dawley rats. AM404 blocks uptake of endocannabinoids and enhances the effects of any endocannabinoids released [M. Beltramo, et al., Functional role of high-affinity anandamide transport, as revealed by selective inhibition, Science 277 (5329) (1997) 1094-1097.] into the NTS. Therefore, it was hypothesized that microinjections of AM404 should exhibit effects similar to microinjections of exogenous AEA. In this study, AM404 microinjections into the NTS were found to significantly prolong baroreflex inhibition of RSNA compared to control, similar to effects of exogenous AEA. This effect is thought to result from an increased endocannabinoid presence in the NTS, leading to prolonged CB(1) receptor activation. These results indicate that endocannabinoids released in the NTS have the potential to modulate baroreflex control at this site in the central baroreflex pathway.     

Socio-demographic and clinical predictors of quality of life in patients with schizophrenia or schizo-affective disorder

This article discusses the relationships between socio-demographic, clinical characteristics and Quality of Life (QOL) of individuals with schizophrenia. The client version of the Canadian version of the Wisconsin Quality of Life Index (CaW-QLI) was used with a population of 182 individuals with either schizophrenia or schizo-affective disorder. Multivariate analyses of variance with Tukey post hoc tests were used to assess differences between groups defined according to socio-demographic and clinical characteristics on all sub-scale scores in addition to the global score on the CaW-QLI. Relationships between socio-demographic characteristics and QOL were found for gender, age, education, employment status and living arrangement. Differences in QOL were found between groups with different clinical characteristics, such as diagnosis, hospitalization during the last 12 months and age at first hospitalization. Using socio-demographic and clinical variables in addition to psychosocial variables appears to be promising for understanding QOL in psychotic patients. Methodological considerations for future research are discussed.     

Cisatracurium pharmacodynamics in patients with oculopharyngeal muscular dystrophy

The pharmacodynamics of muscle relaxants in patients with oculopharyngeal muscular dystrophy (OPMD) have never been studied. We designed this study to compare the pharmacodynamics of cisatracurium in OPMD patients versus a control group. Forty patients were enrolled: 20 OPMD patients requiring general anesthesia for cricopharyngeal myotomy and 20 age-matched controls undergoing an operation of similar duration and expected blood loss. Anesthesia was standardized, and both groups received a bolus of cisatracurium 0.1 mg/kg. Onset time, time to 10% T1 recovery, and the intervals 10%-25% and 25%-75% were calculated for both groups. A subgroup analysis was performed in patients with a more severe form of OPMD. Demographic and intraoperative data were similar. Onset time was significantly longer in OPMD patients compared with the control group (4.6 +/- 1.5 min versus 3.4 +/- 1.0 min; P = 0.001). There was no difference in recovery times or indices between groups, regardless of the severity of the disease. In conclusion, there was no difference in the duration of a cisatracurium-induced neuromuscular block between OPMD patients and a control group. A delayed onset of action of the drug may occur.     

Penny and pound wise: pharmacoeconomics from a governmental perspective

Because of growing pressure on the healthcare budget in The Netherlands, appropriate justification of current expenditures and future investments in public healthcare are becoming increasingly important. Therefore, the Dutch Ministry of Health, Welfare and Sport is expanding its use of pharmacoeconomic evaluation in informed reimbursement decision-making of new pharmaceuticals. Since June 2002, pharmaceutical companies have been invited to submit a pharmacoeconomic dossier with their reimbursement applications of innovative drugs. As of January 2005 submission of a pharmacoeconomic dossier is mandatory for all drugs claiming to have therapeutic value. Currently, several European governmental and non-governmental organisations are making efforts to harmonise pharmacoeconomic research guidelines at the EU level. Ultimately, this may facilitate a more efficient way of conducting pharmacoeconomic research and encourage the use of pharmacoeconomic data by national assessment agencies and governments. It is anticipated that international pharmaceutical companies will increasingly invest in pharmacoeconomics while government staff will become more experienced in appraising the dossiers, thus resulting in an upward momentum in the quality and usability of pharmacoeconomic data. From the Dutch government's perspective, the use of pharmacoeconomic evaluation in reimbursement decision-making should offer a true opportunity for pharmaceutical companies to present the added value for money of new drugs. Using pharmacoeconomic data, costs, benefits and effects of pharmaceuticals are increasingly being considered from a societal perspective, thus going beyond the sole consideration of the impact on the pharmaceutical budget.     

Shunt glomerulonephritis: clinical and histopathological manifestations]

In patients with cerebrospinal fluid internal shunts, immune complex glomerulonephritis sometimes develops. Of two new cases the first was classic, while the second was in an adult who had had a ventriculoatril shunt for 8 years; furthermore, the patient had acute renal failure and is the first to have been reported to have Peptococcus septicemia. Shunt glomerulonephritis is characterized by the following: (a) its occurrence following, most often, Staphylococcus albus infection in a patient who usually has a ventriculoatrial shunt; (b) transitory improvement of the symptoms by antibiotherapy only; and (c) full recovery if the prosthesis is removed. Laboratory studies show a low serum concentration of the C3 component of complement, the presence of cryoglobulins and a positive rheumatoid factor test. These abnormalities are reversible with removal of the prosthesis. Optical microscopy of a renal biopsy specimen in the two cases showed cellular proliferation of the glomerular tuft, electron microscopy demonstrated subepithelial deposits and immunofluorescent studies revealed intramembranous and intramesangial immune complexes. These features are similar to those observed in experimental nephritis induced in animals by foreign protein.