Neuronal sirtuin1 mediates retinal vascular regeneration in oxygen-induced ischemic retinopathy

Regeneration of blood vessels in ischemic neuronal tissue is critical to reduce tissue damage in diseases. In proliferative retinopathy, initial vessel loss leads to retinal ischemia, which can induce either regrowth of vessels to restore normal metabolism and minimize damage, or progress to hypoxia-induced sight-threatening pathologic vaso-proliferation. It is not well understood how retinal neurons mediate regeneration of vascular growth in response to ischemic insults. In this study we aim to investigate the potential role of Sirtuin 1 (Sirt1), a metabolically-regulated protein deacetylase, in mediating the response of ischemic neurons to regulate vascular regrowth in a mouse model of oxygen-induced ischemic retinopathy (OIR). We found that Sirt1 is highly induced in the avascular ischemic retina in OIR. Conditional depletion of neuronal Sirt1 leads to significantly decreased retinal vascular regeneration into the avascular zone and increased hypoxia-induced pathologic vascular growth. This effect is likely independent of PGC-1α, a known Sirt1 target, as absence of PGC-1α in knockout mice does not impact vascular growth in retinopathy. We found that neuronal Sirt1 controls vascular regrowth in part through modulating deacetylation and stability of hypoxia-induced factor 1α and 2α, and thereby modulating expression of angiogenic factors. These results indicate that ischemic neurons induce Sirt1 to promote revascularization into ischemic neuronal areas, suggesting a novel role of neuronal Sirt1 in mediating vascular regeneration in ischemic conditions, with potential implications beyond retinopathy.     

Left ventricular (LV) geometry and dipping state are determinants of LV mass reduction with angiotensin-converting enzyme inhibitor antihypertensive treatment

OBJECTIVES: Left ventricular hypertrophy is a major risk predictor in hypertensive patients and its regression is beneficial in terms of prognosis. The aim of this observational, open-labeled study was to investigate the effect of left ventricular geometry and dipping pattern on left ventricular mass reduction after chronic treatment with angiotensin-converting enzyme inhibitors, in a large population of hypertensive patients. METHODS: We evaluated untreated patients with mild to moderate essential hypertension, before and 6 months after treatment with angiotensin-converting enzyme inhibitor monotherapy or angiotensin-converting enzyme inhibitor-low-dose thiazide combination. Left ventricular mass index, relative wall thickness and geometry pattern were derived from echocardiography. Dipping state was determined with 24-h ambulatory blood pressure monitoring at enrollment. RESULTS: Overall, left ventricular mass index decrease in the 1400 patients (mean age 52.5 years) who completed the study was 12.9% of baseline value (P<0.00001). After adjusting for pretreatment value, left ventricular mass index reduction was similar with all angiotensin-converting enzyme inhibitors used [P= NS (not significant)], but it was higher in nondippers than dippers (14.1 vs. 12.3%, P<0.0001) and in patients with than without baseline left ventricular hypertrophy (14.6 vs. 11.3%, P<0.0001). We observed a stepwise augmentation of left ventricular mass index decrease with worsening left ventricular geometry (P<0.001). In multivariable analysis, impaired left ventricular geometry and blunted nocturnal blood pressure fall before treatment were independent predictors of a high left ventricular mass index reduction after treatment, independent of blood pressure fall, pretreatment left ventricular mass index, and other potential confounders. CONCLUSION: In essential hypertension, left ventricular geometry and dipping state are independent determinants of left ventricular mass reduction with angiotensin-converting enzyme inhibitor treatment. All angiotensin-converting enzyme inhibitors are efficient in decreasing left ventricular mass.     

Development of an immunofiltration-based antigen-detection assay for rapid diagnosis of Ebola virus infection

Ebola virus (EBOV) has caused outbreaks of severe viral hemorrhagic fever in regions of Central Africa where medical facilities are ill equipped and diagnostic capabilities are limited. To obtain a reliable test that can be implemented easily under these conditions, monoclonal antibodies to the EBOV matrix protein (VP40), which previously had been found to work in a conventional enzyme-linked immunosorbent assay, were used to develop an immunofiltration assay for the detection of EBOV antigen in chemically inactivated clinical specimens. The assay was evaluated by use of defined virus stocks and specimens from experimentally infected animals. Its field application was tested during an outbreak of Ebola hemorrhagic fever in 2003. Although the original goal was to develop an assay that would detect all EBOV species, only the Zaire and Sudan species were detected in practice. The assay represents a first-generation rapid field test for the detection of EBOV antigen that can be performed in 30 min without electrical power or expensive or sensitive equipment.     

Nonrandom variability of respiration during sleep in healthy humans

STUDY OBJECTIVES: Breath-to-breath variability is not purely random but is, instead, characterized by correlations on short- and long-term scales. Short-term correlations might reflect intact metabolic-control mechanisms. To investigate whether the higher variability of breathing during rapid eye movement (REM) compared to non-REM (NREM) sleep is of random or nonrandom nature--reflecting an altered respiratory control--short-term and long-term correlations of respiratory drive and timing were determined. DESIGN: A full-night polysomnogram with a pneumotachograph attached to a full-face mask was performed. For each breath during NREM and REM sleep, respiratory components were analyzed based on the quantitative airflow. SETTING: Data collection took place in the sleep laboratory. PARTICIPANTS: Twenty-nine healthy subjects (age, 25.8 +/- 3.1 years). MEASUREMENTS AND RESULTS: Long-term correlations are practically absent in respiratory timing and drive components during NREM sleep, whereas they are present during REM sleep. Short-term correlations are present in respiratory drive, tidal volume, and minute ventilation during both NREM and REM sleep. In all timing components, additional short-term correlations are absent. CONCLUSION: We conclude that from NREM to REM sleep, short-term regulation of respiratory drive remains strongly metabolically controlled and clearly different from the short-term regulation of the rhythm-generating function. Regulation of respiratory timing and drive during REM sleep is characterized by additional long-term correlations. We speculate that this is the result of cortical influences during phasic REM sleep. Thus, the variability of breathing during REM sleep contains a nonrandom component, such that breathing components remain dependent upon each other even with large time lags between components.     

Plasma cell-like morphology of Th1-cytokine-producing cells associated with the loss of CD3 expression

Here we clarified the morphology and phenotype of interleukin (IL)-17- and interferon (IFN)-gamma-producing cells in both in vitro and in vivo situations. Oligoclonal activation of normal peripheral blood mononuclear cells with the superantigen Staphylococcus aureus enterotoxin B and polyclonal activation with phorbol myristate acetate/phytohemagglutinin were used as in vitro models. This study was extended to various in vivo situations such as rheumatoid arthritis, dermatomyositis, and normal activated lymph nodes. The phenotype of IL-17- and IFN-gamma-producing cells was evaluated by immunohistochemistry using the CD3 and CD4 T-cell markers, the CD20, CD38, kappa and lambda light chain B-cell lineage markers. The expression of two chemokine receptors, CCR6 and CCR7, involved with their associated ligands CCL20 and CCL19/CCL21 in the migration of T lymphocytes, was evaluated in tissue sections. After both polyclonal and oligoclonal activation, IL-17+ and IFN-gamma+ cells acquired a plasma cell-like morphology associated with a high secretory activity, the reduced expression of CD3, and no change of CD4 expression. In rheumatoid arthritis, dermatomyositis, and activated lymph nodes, both IL-17- and IFN-gamma-producing cells had the same morphology. These Th1 cytokine-producing cells were CD4(+)-, CD3-, and B-cell lineage marker-negative. In both in vitro and in vivo situations, expression of CCR6 or CCR7 was not associated with a particular subset. In conclusion, activated T-helper CD4(+) T cells, by their release of cytokines, seem to have functional similarities with plasma cells secreting immunoglobulins.     

Keeping with the beat: movement trajectories contribute to movement timing

Previous studies of paced repetitive movements with respect to an external beat have either emphasised (a) the form of movement trajectories or (b) timing errors made with respect to the external beat. The question of what kinds of movement trajectories assist timing accuracy has not previously been addressed. In an experiment involving synchronisation or syncopation with an external auditory metronome we show that the nervous system produces trajectories that are asymmetric with respect to time and velocity in the out and return phases of the repeating movement cycle. This asymmetry is task specific and is independent of motor implementation details (finger flexion vs. extension). Additionally, we found that timed trajectories are less smooth (higher mean squared jerk) than unpaced ones. The degree of asymmetry in the flexion and extension movement times is positively correlated with timing accuracy. Negative correlations were observed between synchronisation timing error and the movement time of the ensuing return phase, suggesting that late arrival of the finger is compensated by a shorter return phase and conversely for early arrival. We suggest that movement asymmetry in repetitive timing tasks helps satisfy requirements of precision and accuracy relative to a target event.