Distinct emphysema subtypes defined by quantitative CT analysis are associated with specific pulmonary matrix metalloproteinases.

BACKGROUND: Emphysema is characterised by distinct pathological sub-types, but little is known about the divergent underlying aetiology. Matrix-metalloproteinases (MMPs) are proteolytic enzymes that can degrade the extracellular matrix and have been identified as potentially important in the development of emphysema. However, the relationship between MMPs and emphysema sub-type is unknown. We investigated the role of MMPs and their inhibitors in the development of emphysema sub-types by quantifying levels and determining relationships with these sub-types in mild-moderate COPD patients and ex/current smokers with preserved lung function. METHODS: Twenty-four mild-moderate COPD and 8 ex/current smokers with preserved lung function underwent high resolution CT and distinct emphysema sub-types were quantified using novel local histogram-based assessment of lung density. We analysed levels of MMPs and tissue inhibitors of MMPs (TIMPs) in bronchoalveolar lavage (BAL) and assessed their relationship with these emphysema sub-types. RESULTS: The most prevalent emphysema subtypes in COPD subjects were mild and moderate centrilobular (CLE) emphysema, while only small amounts of severe centrilobular emphysema, paraseptal emphysema (PSE) and panlobular emphysema (PLE) were present. MMP-3, and -10 associated with all emphysema sub-types other than mild CLE, while MMP-7 and -8 had associations with moderate and severe CLE and PSE. MMP-9 also had associations with moderate CLE and paraseptal emphysema. Mild CLE occurred in substantial quantities irrespective of whether airflow obstruction was present and did not show any associations with MMPs. CONCLUSION: Multiple MMPs are directly associated with emphysema sub-types identified by CT imaging, apart from mild CLE. This suggests that MMPs play a significant role in the tissue destruction seen in the more severe sub-types of emphysema, whereas early emphysematous change may be driven by a different mechanism. TRIAL REGISTRATION: Trial registration number NCT01701869

In vitro selection of miltefosine resistance in promastigotes of Leishmania donovani from Nepal: genomic and metabolomic characterization.

In this study, we followed the genomic, lipidomic and metabolomic changes associated with the selection of miltefosine (MIL) resistance in two clinically derived Leishmania donovani strains with different inherent resistance to antimonial drugs (antimony sensitive strain Sb-S; and antimony resistant Sb-R). MIL-R was easily induced in both strains using the promastigote-stage, but a significant increase in MIL-R in the intracellular amastigote compared to the corresponding wild-type did not occur until promastigotes had adapted to 12.2 μM MIL. A variety of common and strain-specific genetic changes were discovered in MIL-adapted parasites, including deletions at the LdMT transporter gene, single-base mutations and changes in somy. The most obvious lipid changes in MIL-R promastigotes occurred to phosphatidylcholines and lysophosphatidylcholines and results indicate that the Kennedy pathway is involved in MIL resistance. The inherent Sb resistance of the parasite had an impact on the changes that occurred in MIL-R parasites, with more genetic changes occurring in Sb-R compared with Sb-S parasites. Initial interpretation of the changes identified in this study does not support synergies with Sb-R in the mechanisms of MIL resistance, though this requires an enhanced understanding of the parasite's biochemical pathways and how they are genetically regulated to be verified fully.This study was supported by as part of the FP7 EC K aladrug-R project (http://cordis.europa.eu/project/rcn/88823_en.html, grant number: 222895). JAC and MJS are supported by the Wellcome Trust via their core support for the Wellcome Trust Sanger Institute (grant number 098051) . TMF was funded by a BBSRC Research Experience Placement (grant number BB/J014540/1). CJRI was supported by a Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (grant number 101239/Z/13/Z). This research was supported in part by the National Science Foundation (grant number: NSF PHY11-25915) and by the Belgian Science Policy Office (TRIT, contract P7/41, to J-C.D.).This is the final version of the article. It was first available from Wiley via http://dx.doi.org/10.1111/mmi.1329

Differential Expression of Melanopsin Isoforms Opn4L and Opn4S during Postnatal Development of the Mouse Retina

Photosensitive retinal ganglion cells (pRGCs) respond to light from birth and represent the earliest known light detection system to develop in the mouse retina. A number of morphologically and functionally distinct subtypes of pRGCs have been described in the adult retina, and have been linked to different physiological roles. We have previously identified two distinct isoforms of mouse melanopsin, Opn4L and Opn4S, which are generated by alternate splicing of the Opn4 locus. These isoforms are differentially expressed in pRGC subtypes of the adult mouse retina, with both Opn4L and Opn4S detected in M1 type pRGCs, and only Opn4L detected in M2 type pRGCs. Here we investigate the developmental expression of Opn4L and Opn4S and show a differential profile of expression during postnatal development. Opn4S mRNA is detected at relatively constant levels throughout postnatal development, with levels of Opn4S protein showing a marked increase between P0 and P3, and then increasing progressively over time until adult levels are reached by P10. By contrast, levels of Opn4L mRNA and protein are low at birth and show a marked increase at P14 and P30 compared to earlier time points. We suggest that these differing profiles of expression are associated with the functional maturation of M1 and M2 subtypes of pRGCs. Based upon our data, Opn4S expressing M1 type pRGCs mature first and are the dominant pRGC subtype in the neonate retina, whereas increased expression of Opn4L and the maturation of M2 type pRGCs occurs later, between P10 and P14, at a similar time to the maturation of rod and cone photoreceptors. We suggest that the distinct functions associated with these cell types will develop at different times during postnatal development

Alkylation of the Tumor Suppressor PTEN Activates Akt and β-Catenin Signaling: A Mechanism Linking Inflammation and Oxidative Stress with Cancer

PTEN, a phosphoinositide-3-phosphatase, serves dual roles as a tumor suppressor and regulator of cellular anabolic/catabolic metabolism. Adaptation of a redox-sensitive cysteinyl thiol in PTEN for signal transduction by hydrogen peroxide may have superimposed a vulnerability to other mediators of oxidative stress and inflammation, especially reactive carbonyl species, which are commonly occurring by-products of arachidonic acid peroxidation. Using MCF7 and HEK-293 cells, we report that several reactive aldehydes and ketones, e.g. electrophilic α,β-enals (acrolein, 4-hydroxy-2-nonenal) and α,β-enones (prostaglandin A2, Δ12-prostaglandin J2 and 15-deoxy-Δ-12,14-prostaglandin J2) covalently modify and inactivate cellular PTEN, with ensuing activation of PKB/Akt kinase; phosphorylation of Akt substrates; increased cell proliferation; and increased nuclear β-catenin signaling. Alkylation of PTEN by α,β-enals/enones and interference with its restraint of cellular PKB/Akt signaling may accentuate hyperplastic and neoplastic disorders associated with chronic inflammation, oxidative stress, or aging

Medicine in the Popular Press: The Influence of the Media on Perceptions of Disease

In an age of increasing globalization and discussion of the possibility of global pandemics, increasing rates of reporting of these events may influence public perception of risk. The present studies investigate the impact of high levels of media reporting on the perceptions of disease. Undergraduate psychology and medical students were asked to rate the severity, future prevalence and disease status of both frequently reported diseases (e.g. avian flu) and infrequently reported diseases (e.g. yellow fever). Participants considered diseases that occur frequently in the media to be more serious, and have higher disease status than those that infrequently occur in the media, even when the low media frequency conditions were considered objectively ‘worse’ by a separate group of participants. Estimates of severity also positively correlated with popular print media frequency in both student populations. However, we also see that the concurrent presentation of objective information about the diseases can mitigate this effect. It is clear from these data that the media can bias our perceptions of disease

Risk factors for alcohol and other drug use by healthcare professionals

<p>Abstract</p> <p>Background</p> <p>Given the increasingly stressful environment due to manpower shortages in the healthcare system in general, substance induced impairment among some healthcare professions is anticipated to grow. Though recent studies suggest that the prevalence of substance abuse is no higher in healthcare professionals (HPs) than the general population, given the responsibility to the public, any impairment could place the public at increased risk for errors. Few studies have ever reported predictors or risk factors for alcohol and other drug use (AOD) across a sample of HPs.</p> <p>Methods</p> <p>The study used a cross-sectional, descriptive self-report survey in a small northeastern state. A 7-page survey was mailed to a stratified random sample of 697 dentists, nurses, pharmacists and physicians registered in a northeastern state. The main outcome measures were demographic characteristics, lifetime, past year and past month prevalence of AOD use, the frequency of use, drug related dysfunctions, drug misuse and abuse potential. Six contacts during the summer of 2002 resulted in a 68.7% response rate (479/697).</p> <p>Results</p> <p>Risk factors contributing to any reported past year AOD use, as well as significant (defined as the amount of AOD use by the top 25% of respondents) past year AOD use by HPs were examined using logistic regression. Risk factors of any self-reported past year AOD use included moderate or more frequency of alcohol use, being in situations when offered AODs, feeling immune to the addictive effects of drugs (pharmaceutical invincibility) and socializing with substance abusers. Risk factors of significant past year AOD use were HPs with younger licensees, a moderate pattern of alcohol use and not socializing with substance abusers.</p> <p>Conclusion</p> <p>National and state organizations need to develop policies that focus on prevention, treatment, and rehabilitation of alcohol and other drug-using healthcare professionals. The results of this study may help to delineate the characteristics of HPs abusing drugs, leading to the development of more effective policies designed to protect the public, and move toward more tailored and effective intervention strategies for HPs.</p

Invasion is a community affair: clandestine followers in the bacterial community associated to green algae, Caulerpa racemosa, track the invasion source

Biological invasions rank amongst the most deleterious components of global change inducing alterations from genes to ecosystems. The genetic characteristics of introduced pools of individuals greatly influence the capacity of introduced species to establish and expand. The recently demonstrated heritability of microbial communities associated to individual genotypes of primary producers makes them a potentially essential element of the evolution and adaptability of their hosts. Here, we characterized the bacterial communities associated to native and non-native populations of the marine green macroalga Caulerpa racemosa through pyrosequencing, and explored their potential role on the strikingly invasive trajectory of their host in the Mediterranean. The similarity of endophytic bacterial communities from the native Australian range and several Mediterranean locations confirmed the origin of invasion and revealed distinct communities associated to a second Mediterranean variety of C. racemosa long reported in the Mediterranean. Comparative analysis of these two groups demonstrated the stability of the composition of bacterial communities through the successive steps of introduction and invasion and suggested the vertical transmission of some major bacterial OTUs. Indirect inferences on the taxonomic identity and associated metabolism of bacterial lineages showed a striking consistency with sediment upheaval conditions associated to the expansion of their invasive host and to the decline of native species. These results demonstrate that bacterial communities can be an effective tracer of the origin of invasion and support their potential role in their eukaryotic host’s adaptation to new environments. They put forward the critical need to consider the 'meta-organism' encompassing both the host and associated micro-organisms, to unravel the origins, causes and mechanisms underlying biological invasions

Novel Methods for Analysing Bacterial Tracks Reveal Persistence in Rhodobacter sphaeroides

Tracking bacteria using video microscopy is a powerful experimental approach to probe their motile behaviour. The trajectories obtained contain much information relating to the complex patterns of bacterial motility. However, methods for the quantitative analysis of such data are limited. Most swimming bacteria move in approximately straight lines, interspersed with random reorientation phases. It is therefore necessary to segment observed tracks into swimming and reorientation phases to extract useful statistics. We present novel robust analysis tools to discern these two phases in tracks. Our methods comprise a simple and effective protocol for removing spurious tracks from tracking datasets, followed by analysis based on a two-state hidden Markov model, taking advantage of the availability of mutant strains that exhibit swimming-only or reorientating-only motion to generate an empirical prior distribution. Using simulated tracks with varying levels of added noise, we validate our methods and compare them with an existing heuristic method. To our knowledge this is the first example of a systematic assessment of analysis methods in this field. The new methods are substantially more robust to noise and introduce less systematic bias than the heuristic method. We apply our methods to tracks obtained from the bacterial species Rhodobacter sphaeroides and Escherichia coli. Our results demonstrate that R. sphaeroides exhibits persistence over the course of a tumbling event, which is a novel result with important implications in the study of this and similar species