The VLDL receptor promotes lipotoxicity and increases mortality in mice following an acute myocardial infarction

Impaired cardiac function is associated with myocardial triglyceride accumulation, but it is not clear how the lipids accumulate or whether this accumulation is detrimental. Here we show that hypoxia/ischemia-induced accumulation of lipids in HL-1 cardiomyocytes and mouse hearts is dependent on expression of the VLDL receptor (VLDLR). Hypoxia-induced VLDLR expression in HL-1 cells was dependent on HIF-1α through its interaction with a hypoxia-responsive element in the Vldlr promoter, and VLDLR promoted the endocytosis of lipoproteins. Furthermore, VLDLR expression was higher in ischemic compared with nonischemic left ventricles from human hearts and was correlated with the total lipid droplet area in the cardiomyocytes. Importantly, Vldlr-/- mice showed improved survival and decreased infarct area following an induced myocardial infarction. ER stress, which leads to apoptosis, is known to be involved in ischemic heart disease. We found that ischemia-induced ER stress and apoptosis in mouse hearts were reduced in Vldlr-/- mice and in mice treated with antibodies specific for VLDLR. These findings suggest that VLDLR-induced lipid accumulation in the ischemic heart worsens survival by increasing ER stress and apoptosis.     

The effects of alcohol withdrawal on memory,confabulation, and suggestibility

The aim of this study was to investigate the effects of alcohol withdrawal on the accuracy of information obtained during an interview, and in the ability of participants to cope with interrogative pressure. Participants were randomly assigned to one of two groups. Group 1: patients to be tested psychologically on the second or third day of their admission. Group 2: patients who were to be assessed towards the end of their 10-day stay in hospital (i.e. after 6 or more days). The participants were a group of 75 patients admitted as inpatients to a detoxification centre in Iceland. They completed measurements of alcohol withdrawal symptoms, Mini-Mental State, state and trait anxiety, suggestibility, memory, confabulation and compliance. Significant differences emerged, as predicted, with regard to impaired cognitive abilities and heightened anxiety symptoms, but no differences were found for suggestibility, confabulation and compliance. However, a significantly larger Shift score on the Gudjonsson Suggestibility Scale was observed on the third day as an in-patient, as compared with that obtained on the second day of admission and for patients in Group 2. The main conclusion from the study is that, on the third day of detoxification, patients become significantly less able to cope with interrogative pressure. This has practical implications for police interviewing.     

Can individuals with a significant risk for cardiovascular disease be adequately identified by combination of several risk factors? Modelling study based on the Norwegian HUNT 2 population

Rationale, aims and objectives Clinicians are generally advised to consider several risk factors when evaluating patients' cardiovascular disease (CVD) risk. Our aim was to study whether combined assessment of five traditional risk factors might help doctors demarcate a relatively distinct and manageable group of high‐risk individuals. We selected five modifiable risk factors and estimated the proportion of a well‐defined population with ‘unfavourable’ levels of at least two of them, as defined by four internationally renowned guidelines. The impact of including so‐called ‘prehypertension’ among the risk factors was specifically addressed, and the results are discussed in a wider perspective. Material and methods Guideline implementation was modelled on data from a cross‐sectional Norwegian population study comprising 62 104 adults aged 20–79 years (The Nord‐Tröndelag Health Study 1995–7). Total, age‐ and gender‐specific point prevalences of individuals with zero, one, two, three or more factors, in addition to established disease, were calculated. Results One single CVD risk factor was exhibited by 12.4% of the population; two factors by 21.5%; and three or more by 49.7%. Established CVD or diabetes mellitus was reported by 12.5%. In total, 83.7% of the population exhibited a risk or disease profile with at least two factors, if prehypertension was included. Conclusions If guideline recommendations are literally applied, as many as 84% of adults in Norway could exhibit two or more CVD or risk factors and thus be considered in need of individual, clinical attention. This challenges the widely held presumption that ‘the net will close’ around a manageable group of individuals‐at‐risk if several risk factors are jointly considered. As the finding of this study arises in one of the world's most long‐ and healthy‐living populations, it raises several practical as well as ethical questions.     

Comparative effects of thrombopoietic-stimulatory factor and spleen cell-conditioned medium on megakaryocytopoiesis in a short-term bone marrow liquid culture system

The effect of partially purified thrombopoietic stimulatory factor (TSF) on megakaryocytopoiesis was studied using the soft-gel colony-forming assay and a short-term marrow liquid culture system (STLC) and compared to the effects of megakaryocyte colony-stimulating activity present in pokeweed mitogen-stimulated spleen cell-conditioned medium (PWCM). Nonadherent cells from STLC were sampled daily for acetylcholinesterase-positive cells and megakaryocyte progenitor cells (CFU-M). CFU-M were assayed in the soft-gel colony-forming system using PWCM as a source of colony-stimulating activity. Proliferative capacity of CFU-M obtained from liquid culture was determined from megakaryocyte colony size (number of megakaryocytes per colony) following plating of cells in a secondary colony-forming assay. Megakaryocytes were grouped into four maturation classes and megakaryocyte diameter was determined on acetylcholinesterase-stained cytocentrifuged cells using an eye-piece micrometer. TSF produced no CFU-M-derived colonies in the soft-gel colony-forming assay. Addition of TSF to STLC had no effect on the total number of CFU-M, megakaryocyte colony size, or total number of megakaryocytes compared to unstimulated STLC. However, on days 4-9 there was a significant increase in megakaryocyte diameter and the proportion of mature (stage III, IV) megakaryocytes obtained from TSF containing STLC compared to unstimulated STLC. In contrast, 5 days after addition of PWCM to STLC a sixfold increase in the total number of CFU-M per flask and a threefold increase in megakaryocytes was observed compared to unstimulated STLC. However, megakaryocyte colony size and megakaryocyte size were significantly reduced and a greater number of immature (stage I, II) megakaryocytes were present in STLC containing PWCM compared to unstimulated STLC. These results indicate that TSF accelerates the maturation of megakaryocytes in vitro and that a factor or factors present in spleen cell-conditioned medium, in addition to influencing megakaryocyte progenitor cell proliferation, also affect(s) megakaryocyte size.     

Association between glycometabolic status in the acute phase and 2½ years after an acute coronary syndrome

Objectives. To evaluate the association between glycometabolic status in the acute phase and 2½ years later in patients with acute coronary syndrome (ACS). Methods. Non-diabetic patients (n?=?762) presenting with ACS were prospectively followed up for 2½ years. Patients were stratified by admission plasma glucose (<6.1 mmol/l, 6.1 – 6.9 mmol/l and ≥7.0 mmol/l) and HbA1c (≤4.5%, 4.6 – 5.4% and ≥5.5%). The predictive value of glucose levels?≥?7.0 mmol/l and HbA1c?≥?5.5% for glycometabolic disturbance (i.e. diabetes or impaired fasting glycaemia (IFG)) was analysed. Results. Of 762 patients, 13% had a diagnosis of diabetes and 16% had IFG at follow-up. The prevalence of glycometabolic disturbance at follow-up increased with increasing plasma glucose at admission, from 19% in patients with?<?6.1 mmol/l to 42% in patients with?≥?7.0 mmol/l. Sixty-one percent of patients with HbA1c?≥?5.5% had glycometabolic disturbance after 2½ years compared to only 25% of those with HbA1c?<?5.5%. Conclusion. Non-diabetic patients with ACS and hyperglycaemia are at high risk for developing glycometabolic disturbance. HbA1c may be an even stronger predictor of glycometabolic disturbance than plasma glucose.     

No evidence for linkage of schizophrenia to DXS7 at chromosome Xp11

There have been claims that a gene on the X chromosome may contribute to susceptibility to schizophrenia. Crow (1988) initially proposed that such a gene might lie in the pseudoautosomal region, but when evidence that weakened this hypothesis accumulated, he proposed that a susceptibility locus might be present elsewhere on the sex chromosomes instead. DeLisi et al. (1994) found a small nonsignificant positive lod score between the marker DXS7 and schizophrenia, but other failed to replicate this finding. Another study reported by Crow and DeLisi's group was also weakly positive for this marker (Dann et al., 1997). This locus was then investigated in a collaborative study by Laval et al. (1997), which produced a nonparametric lod score of 2.44. Using a sample of 17 pedigrees from Britain and Iceland, we have also tested the hypothesis of linkage between DXS7 and schizophrenia. The 17 families were selected from a larger sample on the basis of an absence of male-to-male transmission for schizophrenia. These families were originally selected for having multiple cases of schizophrenia within them and for having no cases of bipolar affective disorder. We genotyped subjects for a marker at DXS7 and performed classical lod score and model-free linkage analysis using broad and narrow definitions of affection with schizophrenia. We found strongly negative lod scores and no evidence for linkage using model-free analysis. Therefore, this study does not support the hypothesis of linkage of schizophrenia to DXS7, and the evidence for a susceptibility locus on this part of the X chromosome is weakened.