Aquaporin 5 Polymorphisms and Rate of Lung Function Decline in Chronic Obstructive Pulmonary Disease

RATIONALE: Aquaporin-5 (AQP5) can cause mucus overproduction and lower lung function. Genetic variants in the AQP5 gene might be associated with rate of lung function decline in chronic obstructive pulmonary disease (COPD). METHODS: Five single nucleotide polymorphisms (SNPs) in AQP5 were genotyped in 429 European American individuals with COPD randomly selected from the NHLBI Lung Health Study. Mean annual decline in FEV(1) % predicted, assessed over five years, was calculated as a linear regression slope, adjusting for potential covariates and stratified by smoking status. Constructs containing the wildtype allele and risk allele of the coding SNP N228K were generated using site-directed mutagenesis, and transfected into HBE-16 (human bronchial epithelial cell line). AQP5 abundance and localization were assessed by immunoblots and confocal immunofluorescence under control, shear stress and cigarette smoke extract (CSE 10%) exposed conditions to test for differential expression or localization. RESULTS: Among continuous smokers, three of the five SNPs tested showed significant associations (0.02>P>0.004) with rate of lung function decline; no associations were observed among the group of intermittent or former smokers. Haplotype tests revealed multiple association signals (0.012>P>0.0008) consistent with the single-SNP results. In HBE16 cells, shear stress and CSE led to a decrease in AQP5 abundance in the wild-type, but not in the N228K AQP5 plasmid. CONCLUSIONS: Polymorphisms in AQP5 were associated with rate of lung function decline in continuous smokers with COPD. A missense mutation modulates AQP-5 expression in response to cigarette smoke extract and shear stress. These results suggest that AQP5 may be an important candidate gene for COPD

Sensory Stimulation-Dependent Plasticity in the Cerebellar Cortex of Alert Mice

In vitro studies have supported the occurrence of cerebellar long-term depression (LTD), an interaction between the parallel fibers and Purkinje cells (PCs) that requires the combined activation of the parallel and climbing fibers. To demonstrate the existence of LTD in alert animals, we investigated the plasticity of local field potentials (LFPs) evoked by electrical stimulation of the whisker pad. The recorded LFP showed two major negative waves corresponding to trigeminal (broken into the N2 and N3 components) and cortical responses. PC unitary extracellular recording showed that N2 and N3 occurred concurrently with PC evoked simple spikes, followed by an evoked complex spike. Polarity inversion of the N3 component at the PC level and N3 amplitude reduction after electrical stimulation of the parallel fiber volley applied on the surface of the cerebellum 2 ms earlier strongly suggest that N3 was related to the parallel fiber–PC synapse activity. LFP measurements elicited by single whisker pad stimulus were performed before and after trains of electrical stimuli given at a frequency of 8 Hz for 10 min. We demonstrated that during this later situation, the stimulation of the PC by parallel and climbing fibers was reinforced. After 8-Hz stimulation, we observed long-term modifications (lasting at least 30 min) characterized by a specific decrease of the N3 amplitude accompanied by an increase of the N2 and N3 latency peaks. These plastic modifications indicated the existence of cerebellar LTD in alert animals involving both timing and synaptic modulations. These results corroborate the idea that LTD may underlie basic physiological functions related to calcium-dependent synaptic plasticity in the cerebellum

Non-specific interstitial pneumonia in cigarette smokers: a CT study

The goal of this study was to seek indirect evidence that smoking is an aetiological factor in some patients with non-specific interstitial pneumonia (NSIP). Ten current and eight ex-smokers with NSIP were compared to controls including 137 current smokers with no known interstitial lung disease and 11 non-smokers with NSIP. Prevalence and extent of emphysema in 18 smokers with NSIP were compared with subjects meeting GOLD criteria for chronic obstructive pulmonary disease (COPD; group A; n = 34) and healthy smokers (normal FEV1; group B; n = 103), respectively. Emphysema was present in 14/18 (77.8%) smokers with NSIP. Emphysema did not differ in prevalence between NSIP patients and group A controls (25/34, 73.5%), but was strikingly more prevalent in NSIP patients than in group B controls (18/103, 17.5%, P < 0.0005). On multiple logistic regression, the likelihood of emphysema increased when NSIP was present (OR = 18.8; 95% CI = 5.3–66.3; P < 0.0005) and with increasing age (OR = 1.04; 95% CI = 0.99–1.11; P = 0.08). Emphysema is as prevalent in smokers with NSIP as in smokers with COPD, and is strikingly more prevalent in these two groups than in healthy smoking controls. The association between NSIP and emphysema provides indirect support for a smoking pathogenesis hypothesis in some NSIP patients

Personal and Societal Health Quality Lost to Tuberculosis

BACKGROUND: In developed countries, tuberculosis is considered a disease with little loss of Quality-Adjusted Life Years (QALYs). Tuberculosis treatment is predominantly ambulatory and death from tuberculosis is rare. Research has shown that there are chronic pulmonary sequelae in a majority of patients who have completed treatment for pulmonary tuberculosis (PTB). This and other health effects of tuberculosis have not been considered in QALY calculations. Consequently both the burden of tuberculosis on the individual and the value of tuberculosis prevention to society are underestimated. We estimated QALYs lost to pulmonary TB patients from all known sources, and estimated health loss to prevalent TB disease. METHODOLOGY/PRINCIPAL FINDINGS: We calculated values for health during illness and treatment, pulmonary impairment after tuberculosis (PIAT), death rates, years-of-life-lost to death, and normal population health. We then compared the lifetime expected QALYs for a cohort of tuberculosis patients with that expected for comparison populations with latent tuberculosis infection and without tuberculosis infection. Persons with culture-confirmed tuberculosis accrued fewer lifetime QALYs than those without tuberculosis. Acute tuberculosis morbidity cost 0.046 QALYs (4% of total) per individual. Chronic morbidity accounted for an average of 0.96 QALYs (78% of total). Mortality accounted for 0.22 QALYs lost (18% of total). The net benefit to society of averting one case of PTB was about 1.4 QALYs. CONCLUSIONS/SIGNIFICANCE: Tuberculosis, a preventable disease, results in QALYs lost owing to illness, impairment, and death. The majority of QALYs lost from tuberculosis resulted from impairment after microbiologic cure. Successful TB prevention efforts yield more health quality than previously thought and should be given high priority by health policy makers. (Refer to Abstracto S1 for Spanish language abstract)

Climbing Fiber Burst Size and Olivary Sub-threshold Oscillations in a Network Setting

The inferior olivary nucleus provides one of the two main inputs to the cerebellum: the so-called climbing fibers. Activation of climbing fibers is generally believed to be related to timing of motor commands and/or motor learning. Climbing fiber spikes lead to large all-or-none action potentials in cerebellar Purkinje cells, overriding any other ongoing activity and silencing these cells for a brief period of time afterwards. Empirical evidence shows that the climbing fiber can transmit a short burst of spikes as a result of an olivary cell somatic spike, potentially increasing the information being transferred to the cerebellum per climbing fiber activation. Previously reported results from in vitro studies suggested that the information encoded in the climbing fiber burst is related to the occurrence of the spike relative to the ongoing sub-threshold membrane potential oscillation of the olivary cell, i.e. that the phase of the oscillation is reflected in the size of the climbing fiber burst. We used a detailed three-compartmental model of an inferior olivary cell to further investigate the possible factors determining the size of the climbing fiber burst. Our findings suggest that the phase-dependency of the burst size is present but limited and that charge flow between soma and dendrite is a major determinant of the climbing fiber burst. From our findings it follows that phenomena such as cell ensemble synchrony can have a big effect on the climbing fiber burst size through dendrodendritic gap-junctional coupling between olivary cells

X-ray emission from the Sombrero galaxy: discrete sources

We present a study of discrete X-ray sources in and around the bulge-dominated, massive Sa galaxy, Sombrero (M104), based on new and archival Chandra observations with a total exposure of ~200 ks. With a detection limit of L_X = 1E37 erg/s and a field of view covering a galactocentric radius of ~30 kpc (11.5 arcminute), 383 sources are detected. Cross-correlation with Spitler et al.'s catalogue of Sombrero globular clusters (GCs) identified from HST/ACS observations reveals 41 X-rays sources in GCs, presumably low-mass X-ray binaries (LMXBs). We quantify the differential luminosity functions (LFs) for both the detected GC and field LMXBs, whose power-low indices (~1.1 for the GC-LF and ~1.6 for field-LF) are consistent with previous studies for elliptical galaxies. With precise sky positions of the GCs without a detected X-ray source, we further quantify, through a fluctuation analysis, the GC LF at fainter luminosities down to 1E35 erg/s. The derived index rules out a faint-end slope flatter than 1.1 at a 2 sigma significance, contrary to recent findings in several elliptical galaxies and the bulge of M31. On the other hand, the 2-6 keV unresolved emission places a tight constraint on the field LF, implying a flattened index of ~1.0 below 1E37 erg/s. We also detect 101 sources in the halo of Sombrero. The presence of these sources cannot be interpreted as galactic LMXBs whose spatial distribution empirically follows the starlight. Their number is also higher than the expected number of cosmic AGNs (52+/-11 [1 sigma]) whose surface density is constrained by deep X-ray surveys. We suggest that either the cosmic X-ray background is unusually high in the direction of Sombrero, or a distinct population of X-ray sources is present in the halo of Sombrero.Comment: 11 figures, 5 tables, ApJ in pres

Performance of the CMS Cathode Strip Chambers with Cosmic Rays

The Cathode Strip Chambers (CSCs) constitute the primary muon tracking device in the CMS endcaps. Their performance has been evaluated using data taken during a cosmic ray run in fall 2008. Measured noise levels are low, with the number of noisy channels well below 1%. Coordinate resolution was measured for all types of chambers, and fall in the range 47 microns to 243 microns. The efficiencies for local charged track triggers, for hit and for segments reconstruction were measured, and are above 99%. The timing resolution per layer is approximately 5 ns

Ultra-diffuse hydrothermal venting supports Fe-oxidizing bacteria and massive umber deposition at 5000 m off Hawaii

© International Society for Microbial Ecology, 2011. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in The ISME Journal 5 (2011): 1748–1758, doi:10.1038/ismej.2011.48.A novel hydrothermal field has been discovered at the base of Lōihi Seamount, Hawaii, at 5000 mbsl. Geochemical analyses demonstrate that ‘FeMO Deep’, while only 0.2 °C above ambient seawater temperature, derives from a distal, ultra-diffuse hydrothermal source. FeMO Deep is expressed as regional seafloor seepage of gelatinous iron- and silica-rich deposits, pooling between and over basalt pillows, in places over a meter thick. The system is capped by mm to cm thick hydrothermally derived iron-oxyhydroxide- and manganese-oxide-layered crusts. We use molecular analyses (16S rDNA-based) of extant communities combined with fluorescent in situ hybridizations to demonstrate that FeMO Deep deposits contain living iron-oxidizing Zetaproteobacteria related to the recently isolated strain Mariprofundus ferroxydans. Bioenergetic calculations, based on in-situ electrochemical measurements and cell counts, indicate that reactions between iron and oxygen are important in supporting chemosynthesis in the mats, which we infer forms a trophic base of the mat ecosystem. We suggest that the biogenic FeMO Deep hydrothermal deposit represents a modern analog for one class of geological iron deposits known as ‘umbers’ (for example, Troodos ophilolites, Cyprus) because of striking similarities in size, setting and internal structures.Funding has been provided by the NSF Microbial Observatories Program (KJE, DE, BT, HS and CM), by the Gordon and Betty Moore Foundation (KJE), the College of Letters, Arts, and Sciences at the University of Southern California (KJE) and by the NASA Astrobiology Institute (KJE, DE)

Computational Models of Timing Mechanisms in the Cerebellar Granular Layer

A long-standing question in neuroscience is how the brain controls movement that requires precisely timed muscle activations. Studies using Pavlovian delay eyeblink conditioning provide good insight into this question. In delay eyeblink conditioning, which is believed to involve the cerebellum, a subject learns an interstimulus interval (ISI) between the onsets of a conditioned stimulus (CS) such as a tone and an unconditioned stimulus such as an airpuff to the eye. After a conditioning phase, the subject’s eyes automatically close or blink when the ISI time has passed after CS onset. This timing information is thought to be represented in some way in the cerebellum. Several computational models of the cerebellum have been proposed to explain the mechanisms of time representation, and they commonly point to the granular layer network. This article will review these computational models and discuss the possible computational power of the cerebellum