Genetic variation in cholinergic muscarinic-2 receptor gene modulates M2 receptor binding in vivo and accounts for reduced binding in bipolar disorder.

Genetic variation in the cholinergic muscarinic-2 (M(2)) receptor gene (CHRM2) has been associated with the risk for developing depression. We previously reported that M(2)-receptor distribution volume (V(T)) was reduced in depressed subjects with bipolar disorder (BD) relative to depressed subjects with major depressive disorder (MDD) and healthy controls (HCs). In this study, we investigated the effects of six single-nucleotide polymorphisms (SNPs) for CHRM2 on M(2)-receptor binding to test the hypotheses that genetic variation in CHRM2 influences M(2)-receptor binding and that a CHRM2 polymorphism underlies the deficits in M(2)-receptor V(T) observed in BD. The M(2)-receptor V(T) was measured using positron emission tomography and [(18)F]FP-TZTP in unmedicated, depressed subjects with BD (n=16) or MDD (n=24) and HCs (n=25), and the effect of genotype on V(T) was assessed. In the controls, one SNP (with identifier rs324650, in which the ancestral allele adenine (A) is replaced with one or two copies of thymine (T), showed a significant allelic effect on V(T) in the pregenual and subgenual anterior cingulate cortices in the direction AA

Autopsies following death due to traumatic injuries in The Netherlands: an evaluation of current practice.

INTRODUCTION: Because of a steady decline in the number of autopsies following death due to traumatic injuries, valuable information concerning possible missed injuries and potential improvements in management is lost. This retrospective study describes current practice in the Amsterdam region of the Netherlands regarding such autopsies, and their rates. METHOD: The current protocols for autopsies were reviewed. Data from government databases and hospitals for the year 2005 were collected. For all patients included that died an unnatural death due to traumatic injury, causes of death and recommendations for autopsy were reviewed. The number of clinical and medico-legal autopsies was determined. RESULTS: Of 872 registered unnatural deaths, 414 were due to traumatic injuries; 63% of these died before reaching hospital and 37% died in hospital. There were more male deaths, and average age was 54 years. In 23% an autopsy was advised by the medical examiners, more often for pre-hospital deaths. The rate of autopsies was 46% when advice was given for a medico-legal autopsy. CONCLUSION: The rates of both medico-legal and clinically desirable autopsies are very low. Currently, the system in Amsterdam focuses mainly on the former, and the latter with its attendant educational aspects is largely ignored. The role of the government should be expanded to optimise the autopsy system in unnatural deaths following traumatic injuries.

The epidemiology of childhood asthma in Red Deer and Medicine Hat, Alberta.

OBJECTIVES: To document the prevalence of asthma among school-aged children in two Alberta communities, to understand host and indoor environmental factors associated with asthma, and to compare these factors between the two communities. DESIGN: A cross-sectional study with a nested, case-control follow-up. SETTING: Red Deer and Medicine Hat, Alberta. PATIENTS AND METHODS: Questionnaires were sent to families of children aged five to 19 years in Red Deer (n=5292) and Medicine Hat (n=5372) to identify children with current asthma. A random sample of 592 children with current asthma and 443 with no history of asthma constituted a case-control population; they were followed up by telephone to obtain responses to the European Respiratory Health Survey and, in children with current asthma, the Pediatric Quality of Life Questionnaire. RESULTS: Cross-sectional response rates were 84% and 73% for Red Deer and Medicine Hat, respectively. The prevalence of asthma was higher in Medicine Hat (17.0%) than in Red Deer (12.8%). In the follow-up study, factors associated with the presence of asthma were parental asthma or allergies, number of siblings, presence of cats, serious respiratory illnesses before five years of age, sex, age, presence of mould and/or mildew and use of a gas cooking stove. The presence of mould and/or mildew was a significant risk factor in Red Deer but not in Medicine Hat. CONCLUSIONS: Asthma prevalence among school children in Red Deer was consistent with recently published Canadian data; the prevalence in Medicine Hat was higher than expected, especially given the low relative humidity. Risk factor data are consistent with other studies in that parental asthma, especially maternal asthma, was a significant predictor of childhood asthma. Cats in the house (both communities) and environmental tobacco smoke (Medicine Hat only) were significantly less common among children with asthma, suggesting that preventive actions may have been taken in the homes of some children with asthma.

In vitro modulation of microglia motility by glioma cells is mediated by hepatocyte growth factor/scatter factor.

OBJECTIVE: Considered as immune effector cells of the central nervous system, microglia represent a major component of the inflammatory cells found in malignant gliomas. Although their role in brain tumor biology is unclear, accumulation of microglia in malignant brain tumors may be mediated through active secretion of cytokines by glioma cells. Because hepatocyte growth factor/scatter factor (HGF/SF) has been shown to modulate glioma motility through an autocrine mechanism, and because microglia have been reported to express the HGF/SF receptor Met, we hypothesized that microglia recruitment by gliomas may also occur through the secretion of HGF/SF. METHODS: The effect of glioma cells in augmenting BV-2 murine microglia motility was studied by using an in vitro Boyden chamber migration assay. To determine the chemokines involved in microglia migration, neutralizing monoclonal antibodies against monocyte chemotactic protein-1 and HGF/SF were tested. Immunoblotting was used to check for the expression of HGF/SF by glioma cells, and the expression of Met by BV-2 cells was examined by flow cytometry. RESULTS: BV-2 migration was noted within 7 hours of incubation with both human (U251 MG and U373 MG) and murine (GL261) glioma cell lines. This migration corresponded to HGF/SF secretion by glioma cells and was completely inhibited by neutralizing monoclonal antibody against HGF/SF, but not monocyte chemotactic protein-1. Exposure of BV-2 cells to recombinant HGF/SF, but not monocyte chemotactic protein-1, resulted in their migration and down-regulation of Met in a dose-dependent fashion. CONCLUSION: HGF/SF, which plays a role in glioma motility and mitogenesis, may also act as a chemokine for microglia and may be responsible for the microglia infiltration in malignant gliomas. This active recruitment of microglia may play an important role in glioma biology.

Combined radiation and p53 gene therapy of malignant glioma cells.

More than half of malignant gliomas reportedly have alterations in the p53 tumor suppressor gene. Because p53 plays a key role in the cellular response to DNA-damaging agents, we investigated the role of p53 gene therapy before ionizing radiation in cultured human glioma cells containing normal or mutated p53. Three established human glioma cell lines expressing the wild-type (U87 MG, p53wt) or mutant (A172 and U373 MG, p53mut) p53 gene were transduced by recombinant adenoviral vectors bearing human p53 (Adp53) and Escherichia coli beta-galactosidase genes (AdLacZ, control virus) before radiation (0-20 Gy). Changes in p53, p21, and Bax expression were studied by Western immunoblotting, whereas cell cycle alterations and apoptosis were investigated by flow cytometry and nuclear staining. Survival was assessed by clonogenic assays. Within 48 hours of Adp53 exposure, all three cell lines demonstrated p53 expression at a viral multiplicity of infection of 100. p21, which is a p53-inducible downstream effector gene, was overexpressed, and cells were arrested in the G1 phase. Bax expression, which is thought to play a role in p53-induced apoptosis, did not change with either radiation or Adp53. Apoptosis and survival after p53 gene therapy varied. U87 MG (p53wt) cells showed minimal apoptosis after Adp53, irradiation, or combined treatments. U373 MG (p53mut) cells underwent massive apoptosis and died within 48 hours of Adp53 treatment, independent of irradiation. Surprisingly, A172 (p53mut) cells demonstrated minimal apoptosis after Adp53 exposure; however, unlike U373 MG cells, apoptosis increased with radiation dose. Survival of all three cell lines was reduced dramatically after >10 Gy. Although Adp53 transduction significantly reduced the survival of U373 MG cells and inhibited A172 growth, it had no effect on the U87 MG cell line. Transduction with AdLacZ did not affect apoptosis or cell cycle progression and only minimally affected survival in all cell lines. We conclude that responses to p53 gene therapy are variable among gliomas and most likely depend upon both cellular p53 status and as yet ill-defined downstream pathways involving activation of cell cycle regulatory and apoptotic genes.

Restrained eaters are rapidly habituating sensation seekers.

Several authors have pointed to similarities between eating disorders and addictive behaviors. In earlier studies, addicts were found to score high on the Sensation Seeking Scale (SSS) and to habituate rapidly to neutral stimuli. In this study, we found experimental support for an addiction model of eating disorders: restrained eaters also scored significantly higher on the Sensation Seeking Scale and also habituated significantly quicker to a series of neutral stimuli than unrestrained eaters. No clear evidence was found for the hypothesis that restrained eaters score lower on measurements of anxiety. It is hypothesized that rapid habituation promotes sensation seeking, which may be manifested in excessive consumption of either drugs or food. Restraint may be a strategy to prevent negative consequences of sensation seeking and excessive consumption. The model is related to earlier experimental findings.

Blood and plasma viscosity measurements in patients with glaucoma.

Blood viscosity at 10 shear rates, plasma viscosity, packed cell volume, plasma fibrinogen, serum alpha 2-macroglobulin, and serum proteins were measured in 83 patients with low-tension glaucoma (LTG) and 23 patients with 'high-tension glaucoma' (HTG: at least one IOP reading above 40 mmHg) and compared with those in 50 controls. Blood and plasma viscosity values and packed cell volume were significantly higher in the LTG group than those in controls. The HTG and the LTG groups differed only in plasma viscosity, but smoking and drinking habits in the HTG patients were greatly different from those in LTG patients and controls, thus preventing interpretation of data in the HTG group. Within the LTG group viscosity values were highest in a subgroup designated earlier by us as focal ischaemic LTG, whereas another subgroup, senile sclerotic LTG, did not show significant differences compared with controls. These findings may indicate a factor in the pathogenesis of visual field defects and disc cupping in some patients with LTG.

Ten year prospective follow-up of a glaucoma operation. The Double Flap Scheie in primary open angle glaucoma.

The results of a longterm prospective follow-up study after the 'Double Flap' Scheie filtering operation are presented. Fifty-two eyes of 47 patients with primary open angle glaucoma (POAG) were operated; after ten years 29 eyes of 24 patients could be examined. Twenty patients (43%) had died, in three follow-up was incomplete. The two and four year results have been published earlier. In the 29 eyes the mean intraocular pressure (IOP) without medical therapy rose from 15.8 mm Hg at five years to 16.3 mm Hg at ten years (not significant). Additional medical or surgical treatment was necessary in 35% of the eyes. Diurnal variation and outflow facility remained stable. During the ten years 13 eyes showed some deterioration of visual fields. Nearly all clinically important deterioration occurred within five years after the operation. Cataract progression was noticed in 45% (13 of 29); four times a lens extraction was performed (13%). Complete success of the operation, as judged by stable visual fields and IOP levels at or under 21 mm Hg without additional medical or surgical therapy was reached in 13 of 20 eyes (45%). Based on IOP alone the success rate was 62% without and 93% with additional treatment.

[Incidence of various disorders in fattening pigs and their effects on growth and carcass quality]. / Frequentie van enkele aandoeningen bij slachtvarkens en de effecten op groei en slachtkwaliteit.

Findings in 6,304 fattening pigs at the experimental piggery 'Zuid-West Nederland' in Sterksel were used to study the incidence of tail-biting, leg disorders, cough and diarrhoea. The majority of animals were fed ad libitum and housed on completely or partially slatted floors. Approximately 20 per cent of the animals were treated for various conditions. The appearance of these conditions was associated with a decrease in rate of gain of 10-67 g day-1 animal-1. Carcass grading was also reduced in the animals, which had been treated for affections. Tail-biting and diarrhoea were the two most common conditions. The majority of conditions occurred mainly during the first eighty days of the fattening period. However, a higher relative proportion of animals were treated for cough during the last fourty days of the fattening period. Leg-disorders affected the rate of gain more than did the other conditions. The rate of gain was reduced by 67 g day-1 animal-1 and carcass grading by 11 per cent. The conditions were associated with considerable loss in production traits (gain and carcass grading).

Effect of condition of sows on energy balances during 7 days before and 7 days after parturition.

Energy and nitrogen (N) balances were measured in 16 sows from day 106 until day 113 of gestation and from day 2 to day 9 after parturition. Dutch Landrace sows of at least third parity were used, eight animals in poor condition and eight in normal condition. Before parturition, energy and N gain did not depend on the sows' condition. The energy requirement of a sow of 170 kg was met by 2.3 kg of feed per day for the last 10 days of pregnancy. Efficiency of utilization of metabolizable energy for energy gain in conceptus was estimated at about 21%. After parturition, levels of feeding of 2.3 or 4.0 kg per sow per day were used. Each litter was standardized at eight piglets. Energy in sow's milk was negatively correlated with energy balance of sows. Thin sows produced less energy in their milk than normal sows. Efficiency of utilization of metabolizable energy for milk production was calculated as 55 and 70%. Milk was produced from body tissues with an efficiency of 80%. Extra feed for thin sows more adequately prevents protein loss from a sow's body than in normal sows.