REM sleep deprivation inhibits LTP in vivo in area CA1 of rat hippocampus

Rapid eye movement (REM) sleep deprivation has previously been shown to interfere with normal learning and memory and to inhibit long-term potentiation (LTP) in vitro. Previous studies on REM sleep deprivation and LTP have relied on in vitro analysis in isolated brain slices taken from animals following several days of sleep deprivation. LTP in the hippocampus in situ may differ from LTP in vitro due to modulatory inputs from other brain regions, which are altered after REM sleep deprivation. Here, we examined LTP in unanesthetized, behaving animals on the first and second recovery days following REM sleep deprivation to determine if similar effects are seen in vivo as previously reported in vitro. We found that LTP was significantly impaired in REM sleep-deprived animals on the second recovery day but not the first recovery day. Our results extend previous findings by showing that REM sleep deprivation continues to affect hippocampal function for more than 24h following the end of deprivation. Our results also suggest the presence of a modulatory process not present in vitro. Our findings are not explained by stress during REM sleep deprivation because equivalent circulating corticosterone levels (an index of stress) were found during both REM sleep deprivation and control treatment.     

Presenilin regulates extracellular regulated kinase (Erk) activity by a protein kinase C alpha dependent mechanism

Presenilin (PS1 and PS2) mutations cause early-onset familial Alzheimer's disease (AD). In addition to affecting β-amyloid precursor protein (APP) processing and Aβ generation, PSs regulate a number of signaling pathways. We previously showed that PSs regulate both phospholipase C (PLC) and protein kinase C (PKC) α and γ activities. We also reported that PS double knockout mouse embryonic fibroblasts (MEFs) have reduced levels of PKCα and enhanced levels of PKCδ. Here, we determined whether the PS modulation of PLC/PKC has consequences for extracellular regulated kinase (Erk) signaling. Erk has been suggested to be important in AD pathology by modulating APP processing and tau phosphorylation. We found that knocking out PS1 or PS2 alone resulted in increased Erk activity and that this effect could be reversed by the PKCα inhibitor Gö6976. We also found that Erk activity following either PLC or PKC stimulation was significantly lower in PS double knockout cells and that treatment with the PKC activator phorbol 12,13-dibutyrate (PdBu) down-regulated total-Erk levels in all cells except PS double knockouts. These results demonstrate that PSs regulate Erk activity through a PKCα dependent pathway and that disruption of PLC/PKC signaling in the absence of both PS1 and PS2 results in lower downstream activation of Erk.     

Direct toxic effect of iodide in excess on iodine-deficient thyroid glands: epithelial necrosis and inflammation associated with lipofuscin accumulation

Involution of thyroid hyperplasia (induced by a low iodine diet and a goitrogen, propylthiouracil, PTU) was obtained in mice by administering a high or a moderate dose of iodide (HID or MID, respectively). In HID involuting glands, vasoconstriction was observed after 12 hr whereas necrosis and inflammation were very abundant as early as after 6 hr and maximal after 48 hr. They were not prevented by papaverine by which vasoconstriction was inhibited, but were inhibited by the continuation of PTU by which iodide oxidation and organification were inhibited. Lipofuscin inclusions in thyroid and inflammatory cells were always associated with necrosis. On the contrary, when involution was induced by MID or by HID + triiodothyronine (T3), or by T3 alone, neither necrosis nor inflammation occurred and apoptosis was the only mode of cell deletion. No lipofuscin inclusion occurred. Our results demonstrate that iodide in excess, after being oxidized or organified, is directly toxic for iodine-deficient thyroid cells. The presence of lipofuscin suggests that its toxicity is mediated by lipid peroxidation, a consequence of production of free radicals in excess.     

New and sensitive standard cell culture technique for the detection of cytomegalovirus in clinical specimens

Conventional tube cell culture has been recognised as the most sensitive technique available for human cytomegalovirus (HCMV) detection. Low-speed centrifugation of specimen inocula onto cell culture monolayers has been shown to increase the efficiency of infection with the AD 169 strain of HCMV. Therefore a centrifugal force of 900g for 1 hour at 37 degrees C was used to enhance the detection of HCMV cytopathic effect (CPE) in shell vials that contained circular coverslips with a monolayer of human embryonic lung (HEL) fibroblasts. Of 195 specimens, HCMV CPE was detected in 18 specimens (9.02%) on shell vial culture assay, whereas conventional tube cell culture was positive in only 13 specimens (6.6%). The shell vial culture assay was significantly more sensitive (P less than 0.05). Furthermore the development of the cytopathic effect on shell vial culture assay was significantly earlier (P less than 0.01) and more extensive. Urine samples were sonicated and the results obtained with immunofluorescence using human immune serum demonstrated that sonication increased both the intensity of fluorescence and number of fluorescent foci of HCMV-infected cells and also decreased the non-specific fluorescence of the background.     

Human temperature regulation during cycling with moderate leg ischaemia

The effect of graded ischaemia in the legs on the regulation of body temperature during steady-state exercise was investigated in seven healthy males. It was hypothesised that graded ischaemia in the working muscles increases heat storage within the muscles, which in turn potentiates sweat secretion during exercise. Blood perfusion in the working muscles was reduced by applying a supra-atmospheric pressure (+6.6 kPa) around the legs, which reduced maximal working capacity by 29%. Each subject conducted three separate test trials comprising 30 min of steady-state cycling in a supine position. Exercise with unrestricted blood flow (Control trial) was compared to ischaemic exercise conducted at an identical relative work rate (Relative trial), as well as at an identical absolute work rate (Absolute trial); the latter corresponding to a 20% increase in relative workload. The average (SD) increases in both the rectal and oesophageal temperatures during steady-state cycling was 0.3 (0.2)°C and did not significantly differ between the three trials. The increase in muscle temperature was similar in the Control (2.7 (0.3)°C) and Absolute (2.4 (0.7)°C) trials, but was substantially lower (P<0.01) in the Relative trial (1.4 (0.8)°C). Ischaemia potentiated (P<0.01) sweating on the forehead in the Absolute trial (24.2 (7.3) g m^–2 min^–1) compared to the Control trial (13.4 (6.2) g m^–2 min^–1), concomitant with an attenuated (P<0.05) vasodilatation in the skin during exercise. It is concluded that graded ischaemia in working muscles potentiates the exercise sweating response and attenuates vasodilatation in the skin initiated by increased core temperature, effects which may be attributed to an augmented muscle metaboreflex.     

Sputum microbiome profiles identify severe asthma phenotypes of relative stability at 12 to 18 months

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ASSOCIATION OF MHC CLASS I WITH SPONDYLOARTHROPATHIES IN KUWAIT

This study is the first to assess the prevalence of HLA B27 in Kuwaiti patients with ankylosing spondylitis (AS) or related spondyloarthropathies compared to healthy controls. Positive HLA B27 was found in nine (25.7%) of 35 patients, but only in 22 (4%) of 544 controls (P = 0.000). A significant difference in Cw2 and Cw6 between patients and controls was also found (P < 0.01 and 0.000, respectively), suggesting a linkage disequilibrium between B27 and Cw2 (P < 0.000) in the Kuwaiti population. These findings suggest that B27-positive Kuwaitis are at high risk of developing AS and spondyloarthropathies, especially if they carry Cw2 and Cw6. The importance of HLA Cw loci is becoming increasingly apparent in disease association studies.     

Apoptosis in the ovary: molecular mechanisms

Cell death was first described in rabbit ovaries (Graaffian follicles), the phenomenon being called 'chromatolysis' rather than apoptosis. In humans, the ovarian endowment of primordial follicles is established during fetal life. Apoptotic cell death depletes this endowment by at least two-thirds before birth, executed with the help of several players and pathways conserved from worms to humans. To date, apoptosis has been reported to be involved in oogenesis, folliculogenesis, oocyte loss/selection and atresia. Several pro-survival and pro-apoptotic molecules are involved in ovarian apoptosis with the delicate balance between them being the determinant for the final destiny of the follicular cells. This review critically analyses the current knowledge about the biological roles of these molecules and their relevance to the dynamics of follicle development. It also presents the existing literature and assesses the gaps in our knowledge.     

Bone marrow transplantation for diamond-blackfan anemia.

Patients with Diamond-Blackfan anemia (DBA) who are unresponsive to or intolerant of corticosteroids, experience treatment failure with other treatments, develop additional cytopenias or clonal disease, or opt for curative therapy are often treated with allogeneic bone marrow transplantation. We studied the transplantation outcomes of 61 DBA patients whose data were reported to the International Bone Marrow Transplant Registry between 1984 and 2000. The median age was 7 years (range, 1-32 years). Among 55 patients with available transfusion information, 35 (64%) had received > or =20 units of blood before transplantation. Most patients (67%) received their bone marrow grafts from an HLA-matched related donor. The median time to neutrophil recovery was 17 days (range, 10-119 days) and to platelet recovery was 23 days (range, 9-119 days). Five patients did not achieve neutrophil engraftment. The 100-day mortality was 18% (95% confidence interval, 10%-29%). Grade II to IV acute graft-versus-host disease occurred in 28% (range, 17%-39%) and chronic graft-versus-host disease in 26% (range, 15%-39%). The 3-year probability of overall survival was 64% (range, 50%-74%). In univariate analysis, a Karnofsky score > or =90 and transplantation from an HLA-identical sibling donor were associated with better survival. These data suggest that allogeneic bone marrow transplantation is effective for the treatment of DBA. Transplantation before deterioration of the performance status and from an HLA-identical sibling donor may improve survival.