Cathelicidin suppresses lipid accumulation and hepatic steatosis by inhibition of the CD36 receptor.

Background and objectivesObesity is a global epidemic which increases the risk of the metabolic syndrome. Cathelicidin (LL-37 and mCRAMP) is an antimicrobial peptide with an unknown role in obesity. We hypothesize that cathelicidin expression correlates with obesity and modulates fat mass and hepatic steatosis.Materials and methodsMale C57BL/6 J mice were fed a high-fat diet. Streptozotocin was injected into mice to induce diabetes. Experimental groups were injected with cathelicidin and CD36 overexpressing lentiviruses. Human mesenteric fat adipocytes, mouse 3T3-L1 differentiated adipocytes and human HepG2 hepatocytes were used in the in vitro experiments. Cathelicidin levels in non-diabetic, prediabetic and type II diabetic patients were measured by enzyme-linked immunosorbent assay.ResultsLentiviral cathelicidin overexpression reduced hepatic steatosis and decreased the fat mass of high-fat diet-treated diabetic mice. Cathelicidin overexpression reduced mesenteric fat and hepatic fatty acid translocase (CD36) expression that was reversed by lentiviral CD36 overexpression. Exposure of adipocytes and hepatocytes to cathelicidin significantly inhibited CD36 expression and reduced lipid accumulation. Serum cathelicidin protein levels were significantly increased in non-diabetic and prediabetic patients with obesity, compared with non-diabetic patients with normal body mass index (BMI) values. Prediabetic patients had lower serum cathelicidin protein levels than non-diabetic subjects.ConclusionsCathelicidin inhibits the CD36 fat receptor and lipid accumulation in adipocytes and hepatocytes, leading to a reduction of fat mass and hepatic steatosis in vivo. Circulating cathelicidin levels are associated with increased BMI. Our results demonstrate that cathelicidin modulates the development of obesity

Eosinophil and T Cell Markers Predict Functional Decline in COPD Patients

BACKGROUND. The major marker utilized to monitor COPD patients is forced expiratory volume in one second (FEV1). However, asingle measurement of FEV1 cannot reliably predict subsequent decline. Recent studies indicate that T lymphocytes and eosinophils are important determinants of disease stability in COPD. We therefore measured cytokine levels in the lung lavage fluid and plasma of COPD patients in order to determine if the levels of T cell or eosinophil related cytokines were predictive of the future course of the disease. METHODS. Baseline lung lavage and plasma samples were collected from COPD subjects with moderately severe airway obstruction and emphysematous changes on chest CT. The study participants were former smokers who had not had a disease exacerbation within the past six months or used steroids within the past two months. Those subjects who demonstrated stable disease over the following six months (ΔFEV1 % predicted = 4.7 ± 7.2; N = 34) were retrospectively compared with study participants who experienced a rapid decline in lung function (ΔFEV1 % predicted = -16.0 ± 6.0; N = 16) during the same time period and with normal controls (N = 11). Plasma and lung lavage cytokines were measured from clinical samples using the Luminex multiplex kit which enabled the simultaneous measurement of several T cell and eosinophil related cytokines. RESULTS AND DISCUSSION. Stable COPD participants had significantly higher plasma IL-2 levels compared to participants with rapidly progressive COPD (p = 0.04). In contrast, plasma eotaxin-1 levels were significantly lower in stable COPD subjects compared to normal controls (p < 0.03). In addition, lung lavage eotaxin-1 levels were significantly higher in rapidly progressive COPD participants compared to both normal controls (p < 0.02) and stable COPD participants (p < 0.05). CONCLUSION. These findings indicate that IL-2 and eotaxin-1 levels may be important markers of disease stability in advanced emphysema patients. Prospective studies will need to confirm whether measuring IL-2 or eotaxin-1 can identify patients at risk for rapid disease progression.National Heart, Lung, and Blood Institute (NO1-HR-96140, NO1-HR-96141-001, NO1-HR-96144, NO1-HR-96143; NO1-HR-96145; NO1-HR-96142, R01HL086936-03); The Flight Attendant Medical Research Institute; the Jo-Ann F. LeBuhn Center for Chest Diseas

Volatility in the Housing Market: Evidence on Risk and Return in the London Sub-market

The impact of volatility in housing market analysis is reconsidered via examination of the risk-return relationship in the London housing market is examined. In addition to providing the first empirical results for the relationship between risk (as measured by volatility) and returns for this submarket, the analysis offers a more general message to empiricists via a detailed and explicit evaluation of the impact of empirical design decisions upon inferences. In particular, the negative risk-return relationship discussed frequently in the housing market literature is examined and shown to depend upon typically overlooked decisions concerning components of the empirical framework from which statistical inferences are drawn

Estimating the Diets of Animals Using Stable Isotopes and a Comprehensive Bayesian Mixing Model

Using stable isotope mixing models (SIMMs) as a tool to investigate the foraging ecology of animals is gaining popularity among researchers. As a result, statistical methods are rapidly evolving and numerous models have been produced to estimate the diets of animals—each with their benefits and their limitations. Deciding which SIMM to use is contingent on factors such as the consumer of interest, its food sources, sample size, the familiarity a user has with a particular framework for statistical analysis, or the level of inference the researcher desires to make (e.g., population- or individual-level). In this paper, we provide a review of commonly used SIMM models and describe a comprehensive SIMM that includes all features commonly used in SIMM analysis and two new features. We used data collected in Yosemite National Park to demonstrate IsotopeR's ability to estimate dietary parameters. We then examined the importance of each feature in the model and compared our results to inferences from commonly used SIMMs. IsotopeR's user interface (in R) will provide researchers a user-friendly tool for SIMM analysis. The model is also applicable for use in paleontology, archaeology, and forensic studies as well as estimating pollution inputs

Guidelines for delineation of lymphatic clinical target volumes for high conformal radiotherapy: head and neck region

The success of radiotherapy depends on the accurate delineation of the clinical target volume. The delineation of the lymph node regions has most impact, especially for tumors in the head and neck region. The purpose of this article was the development an atlas for the delineation of the clinical target volume for patients, who should receive radiotherapy for a tumor of the head and neck region. Literature was reviewed for localisations of the adjacent lymph node regions and their lymph drain in dependence of the tumor entity. On this basis the lymph node regions were contoured on transversal CT slices. The probability for involvement was reviewed and a recommendation for the delineation of the CTV was generated

Input-specific control of reward and aversion in the ventral tegmental area

Ventral tegmental area (VTA) dopamine neurons have important roles in adaptive and pathological brain functions related to reward and motivation. However, it is unknown whether subpopulations of VTA dopamine neurons participate in distinct circuits that encode different motivational signatures, and whether inputs to the VTA differentially modulate such circuits. Here we show that, because of differences in synaptic connectivity, activation of inputs to the VTA from the laterodorsal tegmentum and the lateral habenula elicit reward and aversion in mice, respectively. Laterodorsal tegmentum neurons preferentially synapse on dopamine neurons projecting to the nucleus accumbens lateral shell, whereas lateral habenula neurons synapse primarily on dopamine neurons projecting to the medial prefrontal cortex as well as on GABAergic (γ-aminobutyric-acid-containing) neurons in the rostromedial tegmental nucleus. These results establish that distinct VTA circuits generate reward and aversion, and thereby provide a new framework for understanding the circuit basis of adaptive and pathological motivated behaviours.National Institutes of Health (U.S.) (Grant NIH NS069375)JPB FoundationNational Institute of Mental Health (U.S.

Exploring variability in the diet of depredating sperm whales in the Gulf of Alaska through stable isotope analysis

Sperm whales interact with commercially important groundfish fisheries offshore in the Gulf of Alaska (GOA). This study aims to use stable isotope analysis to better understand the trophic variability of sperm whales and their potential prey, and to use dietary mixing models to estimate the importance of prey species to sperm whale diets. We analysed tissue samples from sperm whales and seven potential prey (five groundfish and two squid species). Samples were analysed for stable carbon and nitrogen isotope ratios, and diet composition was estimated using Bayesian isotopic mixing models. Mixing model results suggest that an isotopically combined sablefish/ dogfish group, skates and rockfish make up the largest proportion of sperm whale diets (35%, 28% and 12%) in the GOA. The top prey items of whales that interact more frequently with fishing vessels consisted of skates (49%) and the sablefish/dogfish group (24%). This is the first known study to provide an isotopic baseline of adult male sperm whales and these adult groundfish and offshore squid species, and to assign contributions of prey to whale diets in the GOA. This study provides information to commercial fishermen and fisheries managers to better understand trophic connections of important commercial species.Data were collected in collaboration with Cascadia Research Collective, Scripps Institution of Oceanography, Alaska Sea Life Center, Alaska Longline Fishermen’s Association and the Sitka Sound Science Center. SEASWAP co-PIs were all integral in making this project happen: Linda Behnken, Dan Falvey, Victoria O’Connell, Aaron Thode and Russ Andrews. John Calambokidis and Greg Schorr collected biopsy samples used in this project. Kelly Robertson and Gabriela Serra-Valente archived samples at Southwest Fisheries Science Center. Special thanks to the commercial longline fishermen who donated fish and squid that they caught: Frank Balovich and Cale Laduke (F/V Carole D), Paul Ipok (F/V Myra), Walt Cunningham and Jeff Farvour (F/V Christi-Rob), Ryan Nichols (F/V Nekton), Stephen Rhoads and Nick Nekeferof (F/V Magia), Phil Wyman and Kevin Johnson (F/V Archangel), Lucas Skordahl (F/V Tyee), Tyrus Moffitt and Alek Dyakanoff. NMFS GOA longline survey, bottom trawl survey and ecosystem assessment cruise personnel collected specimens: Chris Lunsford, Cindy Tribuzio, Pete Hulson, Dana Hanselman, Cheryl Barnes, Nancy Roberson, Jamal Moss and Wes Strasburger. Laboratory and analysis assistance provided by Illiana Ruiz-Cooley, Todd Miller, Casey Clark, John Logan, Andrew Parnell, Ellen Chenoweth, Madison Kosma, Mike Sigler, Corey Fugate, Matt Rogers, Kate Hauch, Michelle Parke, Kristina Long, Nevé Baker, Emily Whitney and Annie Masterman. Jen Cedarleaf archived historical samples and managed the database. The Inter-Library-Loan folks with the UAF Rasmussen library found all kinds of crazy whaling documents. Finally, special thanks to the Alaska Stable Isotope Facility team of MatWooller, Tim Howe and Norma Haubenstock for their work running bulk isotopes for all of these samples.Ye

Management of patients with persistent medically unexplained symptoms: a descriptive study

Background: In 2013 the Dutch guideline for management of medically unexplained symptoms (MUS) was published. The aim of this study is to assess medical care for patients with persistent MUS as recorded in their electronic medical records, to investigate if this is in line with the national guideline for persistent MUS and whether there are changes in care over time. Methods: We conducted an observational study of adult primary care patients with MUS. Routinely recorded health care data were extracted from electronic medical records of patients participating in an ongoing randomised controlled trial in 30 general practices in the Netherlands. Data on general practitioners’ (GPs’) management strategies during MUS consultations were collected in a 5-year period for each patient prior. Management strategies were categorised according to the options offered in the Dutch guideline. Changes in management over time were analysed. Results: Data were collected from 1035 MUS consultations (77 patients). Beside history-taking, the most frequently used diagnostic strategies were physical examination (24.5%) and additional investigations by the GP (11.1%). Frequently used therapeutic strategies were prescribing medication (24.6%) and providing explanations (11.2%). As MUS symptoms persisted, GPs adjusted medication, discussed progress and scheduled follow-up appointments more frequently. The least frequently used strategies were exploration of all complaint dimensions (i.e. somatic, cognitive, emotional, behavioural and social) (3.5%) and referral to a psychologist (0.5%) or psychiatrist (0.1%). Conclusions: Management of Dutch GPs is partly in line with the Dutch guideline. Medication was possibly prescribed more frequently than recommended, whereas exploration of all complaint dimensions, shared problem definition and referral to mental health care were used less

Orexin-A and Orexin-B During the Postnatal Development of the Rat Brain

Orexin-A and orexin-B are hypothalamic neuropeptides isolated from a small group of neurons in the hypothalamus, which project their axons to all major parts of the central nervous system. Despite the extensive information about orexin expression and function at different parts of the nervous system in adults, data about the development and maturation of the orexin system in the brain are a bit contradictory and insufficient. A previous study has found expression of orexins in the hypothalamus after postnatal day 15 only, while others report orexins detection at embryonic stages of brain formation. In the present study, we investigated the distribution of orexin-A and orexin-B neuronal cell bodies and fibers in the brain at three different postnatal stages: 1-week-, 2-week-old and adult rats. By means of immunohistochemical techniques, we demonstrated that a small subset of cells in the lateral hypothalamus, and the perifornical and periventricular areas were orexin-A and orexin-B positive not only in 2-week-old and adult rats but also in 1-week-old animals. In addition, orexin-A and orexin-B expressing neuronal varicosities were found in many other brain regions. These results suggest that orexin-A and orexin-B play an important role in the early postnatal brain development. The widespread distribution of orexinergic projections through all these stages may imply an involvement of the two neurotransmitters in a large variety of physiological and behavioral processes also including higher brain functions like learning and memory

Molecular and cellular mechanisms underlying the evolution of form and function in the amniote jaw.

The amniote jaw complex is a remarkable amalgamation of derivatives from distinct embryonic cell lineages. During development, the cells in these lineages experience concerted movements, migrations, and signaling interactions that take them from their initial origins to their final destinations and imbue their derivatives with aspects of form including their axial orientation, anatomical identity, size, and shape. Perturbations along the way can produce defects and disease, but also generate the variation necessary for jaw evolution and adaptation. We focus on molecular and cellular mechanisms that regulate form in the amniote jaw complex, and that enable structural and functional integration. Special emphasis is placed on the role of cranial neural crest mesenchyme (NCM) during the species-specific patterning of bone, cartilage, tendon, muscle, and other jaw tissues. We also address the effects of biomechanical forces during jaw development and discuss ways in which certain molecular and cellular responses add adaptive and evolutionary plasticity to jaw morphology. Overall, we highlight how variation in molecular and cellular programs can promote the phenomenal diversity and functional morphology achieved during amniote jaw evolution or lead to the range of jaw defects and disease that affect the human condition