Brainstem prolactin-releasing peptide contributes to cancer anorexia-cachexia syndrome in rats

p to 80% of cancer patients are affected by the cancer anorexia-cachexia syndrome (CACS), which leads to excessive body weight loss, reduced treatment success and increased lethality. The area postrema/nucleus of the solitary tract (AP/NTS) region emerged as a central nervous key structure in this multi-factorial process. Neurons in this area are targeted by cytokines and signal to downstream sites involved in energy homeostasis. NTS neurons expressing prolactin-releasing peptide (PrRP) are implicated in the control of energy intake and hypothalamus-pituitary-adrenal (HPA) axis activation, which contributes to muscle wasting. To explore if brainstem PrRP neurons contribute to CACS, we selectively knocked down PrRP expression in the NTS of hepatoma tumor-bearing rats by an AAV/shRNA gene silencing approach. PrRP knockdown reduced body weight loss and anorexia compared to tumor-bearing controls treated with a non-silencing AAV. Gastrocnemius and total hind limb muscle weight was higher in PrPR knockdown rats. Corticosterone levels were increased in the early phase after tumor induction at day 6 in both groups but returned to baseline levels at day 21 in the PrRP knockdown group. While we did not detect significant changes in gene expression of markers for muscle protein metabolism (MuRF-1, myostatin, mTOR and REDD1), mTOR and REDD1 tended to be lower after disruption PrRP signalling. In conclusion, we identified brainstem PrRP as a possible neuropeptide mediator of CACS in hepatoma tumor-bearing rats. The central and peripheral downstream mechanisms require further investigation and might involve HPA axis activation

Multimodel climate and variability of the stratosphere

The stratospheric climate and variability from simulations of sixteen chemistry‐climate models is evaluated. On average the polar night jet is well reproduced though its variability is less well reproduced with a large spread between models. Polar temperature biases are less than 5 K except in the Southern Hemisphere (SH) lower stratosphere in spring. The accumulated area of low temperatures responsible for polar stratospheric cloud formation is accurately reproduced for the Antarctic but underestimated for the Arctic. The shape and position of the polar vortex is well simulated, as is the tropical upwelling in the lower stratosphere. There is a wide model spread in the frequency of major sudden stratospheric warnings (SSWs), late biases in the breakup of the SH vortex, and a weak annual cycle in the zonal wind in the tropical upper stratosphere. Quantitatively, “metrics” indicate a wide spread in model performance for most diagnostics with systematic biases in many, and poorer performance in the SH than in the Northern Hemisphere (NH). Correlations were found in the SH between errors in the final warming, polar temperatures, the leading mode of variability, and jet strength, and in the NH between errors in polar temperatures, frequency of major SSWs, and jet strength. Models with a stronger QBO have stronger tropical upwelling and a colder NH vortex. Both the qualitative and quantitative analysis indicate a number of common and long‐standing model problems, particularly related to the simulation of the SH and stratospheric variability

Multimodel assessment of the upper troposphere and lower stratosphere: Extratropics

A multimodel assessment of the performance of chemistry-climate models (CCMs) in the extratropical upper troposphere/lower stratosphere (UTLS) is conducted for the first time. Process-oriented diagnostics are used to validate dynamical and transport characteristics of 18 CCMs using meteorological analyses and aircraft and satellite observations. The main dynamical and chemical climatological characteristics of the extratropical UTLS are generally well represented by the models, despite the limited horizontal and vertical resolution. The seasonal cycle of lowermost stratospheric mass is realistic, however with a wide spread in its mean value. A tropopause inversion layer is present in most models, although the maximum in static stability is located too high above the tropopause and is somewhat too weak, as expected from limited model resolution. Similar comments apply to the extratropical tropopause transition layer. The seasonality in lower stratospheric chemical tracers is consistent with the seasonality in the Brewer-Dobson circulation. Both vertical and meridional tracer gradients are of similar strength to those found in observations. Models that perform less well tend to use a semi-Lagrangian transport scheme and/or have a very low resolution. Two models, and the multimodel mean, score consistently well on all diagnostics, while seven other models score well on all diagnostics except the seasonal cycle of water vapor. Only four of the models are consistently below average. The lack of tropospheric chemistry in most models limits their evaluation in the upper troposphere. Finally, the UTLS is relatively sparsely sampled by observations, limiting our ability to quantitatively evaluate many aspects of model performance

Treatment of American tegumentary leishmaniasis in special populations : a summary of evidence

We aimed to assess and synthesize the information available in the literature regarding the treatment of American tegumentary leishmaniasis in special populations. We searched MEDLINE (via PubMed), EMBASE, LILACS, SciELO, Scopus, Cochrane Library and mRCT databases to identify clinical trials and observational studies that assessed the pharmacological treatment of the following groups of patients: pregnant women, nursing mothers, children, the elderly, individuals with chronic diseases and individuals with suppressed immune systems. The quality of evidence was assessed using the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) approach. The available evidence suggests that the treatments of choice for each population or disease entity are as follows: nursing mothers and children (meglumine antimoniate or pentamidine), patients with renal disease (amphotericin B or miltefosine), patients with heart disease (amphotericin B, miltefosine or pentamidine), immunosuppressed patients (liposomal amphotericin), the elderly (meglumine antimoniate), pregnant women (amphotericin B) and patients with liver disease (no evidence available). The quality of evidence is low or very low for all groups. Accurate controlled studies are required to fill in the gaps in evidence for treatment in special populations. Post-marketing surveillance programs could also collect relevant information to guide treatment decision-making

Early diagnosis of temporomandibular joint involvement in juvenile idiopathic arthritis: a pilot study comparing clinical examination and ultrasound to magnetic resonance imaging

OBJECTIVES: To study the validity of both rheumatological and orthodontic examinations and ultrasound (US) as screening methods for early diagnosis of TMJ arthritis against the gold standard MRI. METHODS: Thirty consecutive juvenile idiopathic arthritis (JIA) patients were included in this pilot study. Rheumatological and orthodontic examinations as well as US were performed within 1 month of the MRI in a blinded fashion. Joint effusion and/or increased contrast enhancement of synovium or bone were considered signs of active arthritis on MRI. RESULTS: A total of 19/30 (63%) patients and 33/60 (55%) joints had signs of TMJ involvement on MRI. This was associated with condylar deformity in 9/19 (47%) patients and 15/33 (45%) joints. Rheumatological, orthodontic and US examinations correctly diagnosed 11 (58%), 9 (47%) and 6 (33%) patients, respectively, with active TMJ arthritis, but misdiagnosed 8 (42%), 10 (53%) and 12 (67%) patients, respectively, as having no signs of inflammation. The best predictor for active arthritis on MRI was a reduced maximum mouth opening. CONCLUSION: None of the methods tested was able to reliably predict the presence or absence of MRI-proven inflammation in the TMJ in our cohort of JIA patients. US was the least useful of all methods tested to exclude active TMJ arthritis

The simulation of the Antarctic ozone hole by chemistry-climate models

International audienceWhile chemistry-climate models are able to reproduce many characteristics of the global total column ozone field and its long-term evolution, they have fared less well in simulating the commonly used diagnostic of the area of the Antarctic ozone hole i.e. the area within the 220 Dobson Unit (DU) contour. Two possible reasons for this are: (1) the underlying Global Climate Model (GCM) does not correctly simulate the size of the polar vortex, and (2) the stratospheric chemistry scheme incorporated into the GCM, and/or the model dynamics, results in systematic biases in the total column ozone fields such that the 220 DU contour is no longer appropriate for delineating the edge of the ozone hole. Both causes are examined here with a view to developing ozone hole area diagnostics that better suit measurement-model inter-comparisons. The interplay between the shape of the meridional mixing barrier at the edge of the vortex and the meridional gradients in total column ozone across the vortex edge is investigated in measurements and in 5 chemistry-climate models (CCMs). Analysis of the simulation of the polar vortex in the CCMs shows that the first of the two possible causes does play a role in some models. This in turn affects the ability of the models to simulate the large observed meridional gradients in total column ozone. The second of the two causes also strongly affects the ability of the CCMs to track the observed size of the ozone hole. It is shown that by applying a common algorithm to the CCMs for selecting a delineating threshold unique to each model, a more appropriate diagnostic of ozone hole area can be generated that shows better agreement with that derived from observations