Gene delivery of human apolipoprotein E alters brain Abeta burden in a mouse model of Alzheimer's disease

Apolipoprotein E (apoE) alleles are important genetic risk factors for Alzheimer's disease (AD), with the epsilon4 allele increasing and the epsilon2 allele decreasing risk for developing AD. ApoE has been shown to influence brain amyloid-beta peptide (Abeta) and amyloid burden, both in humans and in transgenic mice. Here we show that direct intracerebral administration of lentiviral vectors expressing the three common human apoE isoforms differentially alters hippocampal Abeta and amyloid burden in the PDAPP mouse model of AD. Expression of apoE4 in the absence of mouse apoE increases hippocampal Abeta(1-42) levels and amyloid burden. By contrast, expression of apoE2, even in the presence of mouse apoE, markedly reduces hippocampal Abeta burden. Our data demonstrate rapid apoE isoform-dependent effects on brain Abeta burden in a mouse model of AD. Gene delivery of apoE2 may prevent or reduce brain Abeta burden and the subsequent development of neuritic plaques.     

Passive elastic wall properties in isolated guinea pig small intestine

The aim was to study and compare the passive biomechanical wall properties in the isolated duodenum and distal ileum of the guinea pigin vitro. The organ bath contained a Krebs-Ringer solution with 10^?2 M MgCl₂ to abolish smooth muscle contractile activity. Stepwise inflation of an intraluminal balloon, in which the cross-sectional area (CSA) was measured, provided the distension stimulus. The circumferential wall tension-strain distributions and wall stiffness-strain relations were computed from steady-state values of these measurements in order to evaluate the passive elastic properties. The CSA always reached equilibrium within the 2-min distension period. The CSAs obtained in the distal ileum were higher than those in the duodenum (P<0.001). The basal CSA was 17.31±1.14 mm² and 12.96±0.42 mm² for the distal ileum and the duodenum, respectively (P<0.01). At a maximum pressure of 6 kPa, the CSA of the ileum was 56.63±1.81 mm² and 36.86±1.76 mm² for the duodenum (P<0.01). The circumferential wall tension-strain distributions showed an exponential behavior that accorded well with the equationY=exp(a+bX) with determination coefficients of 0.96±0.01 and 0.99±0.00 in the duodenal segments in the distal ileal segments, respectively. The values ofa (intercept with they-axis) were 0.54±0.11 and ?0.35±0.19 for the duodenal and ileal segments, respectively (P<0.001). The slope of the curves (b values) were 4.34±0.35 in the duodenal and 5.23±0.37 in the ileal segments (0.1>P>0.05). In conclusion, differences in elastic properties were found between the proximal and distal small intestine.     

Remodelling of zero-stress state of small intestine in streptozotocin-induced diabetic rats. Effect of gliclazide

BACKGROUND: Biomechanical properties in terms of residual strains in diabetic small intestine have not been studied. Furthermore, no data have been reported on affect of gliclazide on gastrointestinal complications of diabetes. AIMS: To determine remodelling of zero-stress state of small intestine in streptozotocin-induced diabetic rats and effect of gliclazide treatment. MATERIALS: Morphological properties and residual strains were studied in duodenum, jejunum and ileum obtained from diabetic rats, gliclazide-treated diabetic rats and normal rats (n = 8 each group). METHODS: Diabetes was induced by single intraperitoneal injection of 65 mg/kg streptozotocin. Gliclazide (10 mg kg(-1) day(-1) was injected directly into stomach lumen by intragastric gavage twice daily. Experimental period was 35 days. To approach no-load state; intestinal segments were surgically excised and cut transversely into short ring-shaped segments. Each ring was cut radially to obtain geometry of zero-stress state. Circumferential length, the wall thickness and opening angle were measured from digital images of each specimen and residual strains were computed. RESULTS: Blood glucose level of diabetic group (approximately 20 mmol/l) was consistently higher than that in normal group (approximately 4 mmol/l) after induction of diabetes (p < 0.001). Gliclazide lowered average blood glucose level to between 10 and 15 mmol/l (p < 0.001). Plasma insulin levels of both diabetic groups (average between 10 and 15 pmol/l) were significantly lower than those in normal group (average approximately 18 pmol/l, p < 0.05). Wet weight per unit length and wall thickness of duodenum, jejunum and ileum were significantly higher in Diabetes group than those in Normal group (p < 0.05). Opening angle and absolute value of residual strain were significantly smaller in duodenum and larger in jejunum and ileum in Diabetes group than in Normal group (p < 0.001). Gliclazide treatment partly restored these changes (p < 0.05). CONCLUSIONS: Diabetes induced morphometric and biomechanical remodelling in intestine. Gliclazide partly restored these changes.     

Does esophageal function vary at the striated and smooth muscle segments in functional chest pain?

OBJECTIVE: Hypersensitivity of the esophageal wall may contribute to the pathogenesis of functional chest pain. Whether the hypersensitivity is more uniformly distributed along the esophageal wall or is segmental is not known. METHODS: Graded balloon distentions were performed randomly at the smooth muscle as well as at the striated muscle portions of the esophagus in 20 patients with functional chest pain and in 15 healthy volunteers, using impedance planimetry. Sensory thresholds and cross-sectional area were examined in relation to the esophageal wall tension, and the results were compared between two levels as well as the two groups of subjects. RESULTS: During balloon distention, 17 (85%) patients reported typical chest pain, 11 (55%) at both levels, four (20%) at the smooth muscle level, and two (10%) at the striated muscle level only. The sensory thresholds for perception, discomfort, or pain were lower in patients than in controls (p < 0.05). The cross-sectional area and the esophageal wall stiffness at the smooth muscle level were lower than those obtained at the striated muscle level both in controls and in patients (p < 0.01). The wall tension at which moderate discomfort and pain were reported was lower in patients than controls (p < 0.05). CONCLUSIONS: Although in most patients the esophagus is uniformly hypersensitive, in some either the smooth muscle or the striated muscle segment can be hypersensitive. If considering balloon distention at only one level, we recommend balloon placement at 10 cm above the lower esophageal sphincter because of a higher yield of hypersensitivity.     

The Association Between Serum Calcium Levels and Short-Term Mortality in Patients with Chronic Heart Failure

Background

Patients with chronic heart failure have vulnerable myocardial function and are susceptible to electrolyte disturbances. In these patients, diuretic treatment is frequently prescribed, though it is known to cause electrolyte disturbances. Therefore, we investigated the association between altered calcium homeostasis and the risk of all-cause mortality in chronic heart failure patients.

The Intentional Differences: A Qualitative Study of the Views and Experiences of Non-peer Mental Health Providers on Working Together with Peer Support Colleagues in Mental Health

Community Mental Health Journal - The study reports the results of a qualitative study on the views and experiences of non-peer mental health providers on working together with peer colleagues in...     

Mutations in SYNGAP1 Cause Intellectual Disability,Autism, and a Specific Form of Epilepsy by Inducing Haploinsufficiency

De novo mutations in SYNGAP1, which codes for a RAS/RAP GTP‐activating protein, cause nonsyndromic intellectual disability (NSID). All disease‐causing point mutations identified until now in SYNGAP1 are truncating, raising the possibility of an association between this type of mutations and NSID. Here, we report the identification of the first pathogenic missense mutations (c.1084T>C [p.W362R], c.1685C>T [p.P562L]) and three novel truncating mutations (c.283dupC [p.H95PfsX5], c.2212_2213del [p.S738X], and (c.2184del [p.N729TfsX31]) in SYNGAP1 in patients with NSID. A subset of these patients also showed ataxia, autism, and a specific form of generalized epilepsy that can be refractory to treatment. All of these mutations occurred de novo, except c.283dupC, which was inherited from a father who is a mosaic. Biolistic transfection of wild‐type SYNGAP1 in pyramidal cells from cortical organotypic cultures significantly reduced activity‐dependent phosphorylated extracellular signal‐regulated kinase (pERK) levels. In contrast, constructs expressing p.W362R, p.P562L, or the previously described p.R579X had no significant effect on pERK levels. These experiments suggest that the de novo missense mutations, p.R579X, and possibly all the other truncating mutations in SYNGAP1 result in a loss of its function. Moreover, our study confirms the involvement of SYNGAP1 in autism while providing novel insight into the epileptic manifestations associated with its disruption.     

Schizophrenia and Metacognition: An Investigation of Course of Illness and Metacognitive Beliefs Within a First Episode Psychosis

Cognitive Therapy and Research - The Self Regulatory Executive Function (S-REF) model implicates maladaptive metacognitive beliefs and processes in the predisposition and/or maintenance of positive...     

Postoperative blood transfusion strategy in frail,anemic elderly patients with hip fracture

Background and purpose — Hip fracture (HF) in frail elderly patients is associated with poor physical recovery and death. There is often postoperative blood loss and the hemoglobin (Hb) threshold for red blood cell (RBC) transfusions in these patients is unknown. We investigated whether RBC transfusion strategies were associated with the degree of physical recovery or with reduced mortality after HF surgery.

Patients and methods — We enrolled 284 consecutive post-surgical HF patients (aged ≥ 65 years) with Hb levels < 11.3 g/dL (7 mmol/L) who had been admitted from nursing homes or sheltered housing. Allocation was stratified by residence. The patients were randomly assigned to either restrictive (Hb < 9.7 g/dL; < 6 mmol/L) or liberal (Hb < 11.3 g/dL; < 7 mmol/L) RBC transfusions given within the first 30 days postoperatively. Follow-up was at 90 days.

Results — No statistically significant differences were found in repeated measures of daily living activities or in 90-day mortality rate between the restrictive group (where 27% died) and the liberal group (where 21% died). Per-protocol 30-day mortality was higher with the restrictive strategy (hazard ratio (HR) = 2.4, 95% CI: 1.1–5.2; p = 0.03). The 90-day mortality rate was higher for nursing home residents in the restrictive transfusion group (36%) than for those in the liberal group (20%) (HR = 2.0, 95% CI: 1.1–3.6; p = 0.01).

Interpretation — According to our Hb thresholds, recovery from physical disabilities in frail elderly hip fracture patients was similar after a restrictive RBC transfusion strategy and after a liberal strategy. Implementation of a liberal RBC transfusion strategy in nursing home residents has the potential to increase survival.