Temperature but not leptin prevents semi-starvation induced hyperactivity in rats: implications for anorexia nervosa treatment

The hypothesis linking hyperactivity with weight loss associated hypoleptinemia in anorexia nervosa gained momentum after a study showing that leptin suppressed semi-starvation induced hyperactivity in rats. Alternatively, ambient temperature is a key modulating factor of activity in semi-starved rats. The aim of the study is to compare the efficacy of leptin with increased ambient temperature in the prevention of hyperactivity in semi-starved rats. 74 Sprague-Dawley male rats were employed in two experiments with the difference residing in the length of baseline. After an extended (28 days), or shorter (14 days) baseline with free access to food and the running wheel, housed at 21 degrees C, animals were either ad-lib feed or food restricted (60% of food ingested during previous week) and infused with same amount of leptin at 21 degrees C, 25 degrees C, or vehicle at 21 degrees C, 25 degrees C and 32 degrees C for a week. Animals housed at 32 degrees C significantly reduced wheel running and weight loss during food restriction while animals given leptin did not yield no differences in activity or weight loss. Moreover, unlike animals housed at 32 degrees C, body temperature of leptin infused animals housed at 21 degrees C was significantly reduced during food restriction. Furthermore, leptin treated rats without a preceding stable pattern of activity displayed a severe dysregulation of circadian rhythm in activity and a collapse of body temperature. Housing temperature plays a more critical role than leptin in the regulation of semi-starvation induced hyperactivity in rats, which may be of relevance for the management of hyperactivity in anorexia nervosa

Pathogenesis and Clinical Relevance of Candida Biofilms in Vulvovaginal Candidiasis

The ability of Candida spp. to form biofilms is crucial for its pathogenicity, and thus, it should be considered an important virulence factor in vulvovaginal candidiasis (VVC) and recurrent VVC (RVVC). Its ability to generate biofilms is multifactorial and is generally believed to depend on the site of infection, species and strain involved, and the microenvironment in which the infection develops. Therefore, both cell surface proteins, such as Hwp1, Als1, and Als2, and the cell wall-related protein, Sun41, play a critical role in the adhesion and virulence of the biofilm. Immunological and pharmacological approaches have identified the NLRP3 inflammasome as a crucial molecular factor contributing to host immunopathology. In this context, we have earlier shown that Candida albicans associated with hyphae-secreted aspartyl proteinases (specifically SAP4-6) contribute to the immunopathology of the disease. Transcriptome profiling has revealed that non-coding transcripts regulate protein synthesis post-transcriptionally, which is important for the growth of Candida spp. Other studies have employed RNA sequencing to identify differences in the 1,245 Candida genes involved in surface and invasive cellular metabolism regulation. In vitro systems allow the simultaneous processing of a large number of samples, making them an ideal screening technique for estimating various physicochemical parameters, testing the activity of antimicrobial agents, and analyzing genes involved in biofilm formation and regulation (in situ) in specific strains. Murine VVC models are used to study C. albicans infection, especially in trials of novel treatments and to understand the cause(s) for resistance to conventional therapeutics. This review on the clinical relevance of Candida biofilms in VVC focuses on important advances in its genomics, transcriptomics, and proteomics. Moreover, recent experiments on the influence of biofilm formation on VVC or RVVC pathogenesis in laboratory animals have been discussed. A clear elucidation of one of the pathogenesis mechanisms employed by Candida biofilms in vulvovaginal candidiasis and its applications in clinical practice represents the most significant contribution of this manuscript

Epigenetic Silencing of Tumor Suppressor miR-124 Directly Supports STAT3 Activation in Cutaneous T-Cell Lymphoma

Increasing evidence supports a potential role for STAT3 as a tumor driver in cutaneous T-cell lymphomas (CTCL). The mechanisms leading to STAT3 activation are not fully understood; however, we recently found that miR-124, a known STAT3 regulator, is robustly silenced in MF tumor-stage and CTCL cells. OBJECTIVE: We studied here whether deregulation of miR-124 contributes to STAT3 pathway activation in CTCL. METHODS: We measured the effect of ectopic mir-124 expression in active phosphorylated STAT3 (p-STAT3) levels and evaluated the transcriptional impact of miR-124-dependent STAT3 pathway regulation by expression microarray analysis. RESULTS: We found that ectopic expression of miR-124 results in massive downregulation of activated STAT3 in different CTCL lines, which resulted in a significant alteration of genetic signatures related with gene transcription and proliferation such as MYC and E2F. CONCLUSIONS: Our study highlights the importance of the miR-124/STAT3 axis in CTCL and demonstrates that the STAT3 pathway is regulated through epigenetic mechanisms in these cells. Since deregulated STAT3 signaling has a major impact on CTCL initiation and progression, a better understanding of the molecular basis of the miR-124/STAT3 axis may provide useful information for future personalized therapies

COVID-19 and Sick Leave: An Analysis of the Ibermutua Cohort of Over 1,651,305 Spanish Workers in the First Trimester of 2020

Objectives: The worldwide SARS-COV2 pandemic has impacted the health of workers and companies. The aim is to quantify it according to sick leave. Methods: Using ICD-9 codes, we analyzed Ibermutua records of all sick leaves during the first trimester of 2020, compared to during the same months of 2017, 2018, and 2019. We stratified the analysis by causes, patient sex, activity sectors, and regional data. All sick leaves were adjusted by the number of Ibermutua-affiliated persons in each period. Results: In March 2020, there was an unprecedented (116%) increase in total sick leaves, mainly due to infectious and respiratory diseases. Men and women were equally affected. All activity sectors were impacted, with the highest increase (457%) observed among health-related workers, especially due to contagious disease. The incidences of sick leaves were heterogeneous among different regions. Cost-analysis of sick leaves during the first trimester of 2020 compared with in previous years showed 40.3% increment (mean 2,813 vs. 2,005 euro per 100 affiliated workers). Conclusions: The SARS-COV2 pandemic is having a huge impact on workers' health, as shown by data regarding sick leaves in March 2020. This is associated with greater economic burden for companies, both due to the cost associated with sick leaves and the losses in productivity due to confinement

Follow-up observations at 16 and 33 GHz of extragalactic sources from WMAP 3-year data: I - Spectral properties

We present follow-up observations of 97 point sources from the Wilkinson Microwave Anisotropy Probe (WMAP) 3-year data, contained within the New Extragalactic WMAP Point Source (NEWPS) catalogue between declinations of -4 and +60 degrees; the sources form a flux-density-limited sample complete to 1.1 Jy (approximately 5 sigma) at 33 GHz. Our observations were made at 16 GHz using the Arcminute Microkelvin Imager (AMI) and at 33 GHz with the Very Small Array (VSA). 94 of the sources have reliable, simultaneous -- typically a few minutes apart -- observations with both telescopes. The spectra between 13.9 and 33.75 GHz are very different from those of bright sources at low frequency: 44 per cent have rising spectra (alpha < 0.0), where flux density is proportional to frequency^-alpha, and 93 per cent have spectra with alpha < 0.5; the median spectral index is 0.04. For the brighter sources, the agreement between VSA and WMAP 33-GHz flux densities averaged over sources is very good. However, for the fainter sources, the VSA tends to measure lower values for the flux densities than WMAP. We suggest that the main cause of this effect is Eddington bias arising from variability.Comment: 12 pages, 13 figures, submitted to MNRA

XPO1 Gene Therapy Attenuates Cardiac Dysfunction in Rats with Chronic Induced Myocardial Infarction

Transcriptomic signature of XPO1 was highly expressed and inversely related to left ventricular function in ischemic cardiomyopathy patients. We hypothesized that treatment with AAV9-shXPO1 attenuates left ventricular dysfunction and remodeling in a myocardial infarction rat model. We induced myocardial infarction by coronary ligation in Sprague-Dawley rats (n = 10), which received AAV9-shXPO1 (n = 5) or placebo AAV9-scramble (n = 5) treatment. Serial echocardiographic assessment was performed throughout the study. After myocardial infarction, AAV9-shXPO1-treated rats showed partial recovery of left ventricular fractional shortening (16.8 +/- 2.8 vs 24.6 +/- 4.1%, P < 0.05) and a maintained left ventricular dimension (6.17 +/- 0.95 vs 4.70 +/- 0.93 mm, P < 0.05), which was not observed in non-treated rats. Furthermore, lower levels of EXP-1 (P < 0.05) and lower collagen fibers and fibrosis in cardiac tissue were observed. However, no differences were found in the IL-6 or TNFR1 plasma levels of the myocardium of AAV9-shXPO1 rats. AAV9-shXPO1 administration attenuates cardiac dysfunction and remodeling in rats after myocardial infarction, producing the gene silencing of XPO1

Rapid Phenotype-Driven Gene Sequencing with the NeoSeq Panel: A Diagnostic Tool for Critically Ill Newborns with Suspected Genetic Disease

New genomic sequencing techniques have shown considerable promise in the field of neonatology, increasing the diagnostic rate and reducing time to diagnosis. However, several obstacles have hindered the incorporation of this technology into routine clinical practice. We prospectively evaluated the diagnostic rate and diagnostic turnaround time achieved in newborns with suspected genetic diseases using a rapid phenotype-driven gene panel (NeoSeq) containing 1870 genes implicated in congenital malformations and neurological and metabolic disorders of early onset (<2 months of age). Of the 33 newborns recruited, a genomic diagnosis was established for 13 (39.4%) patients (median diagnostic turnaround time, 7.5 days), resulting in clinical management changes in 10 (76.9%) patients. An analysis of 12 previous prospective massive sequencing studies (whole genome (WGS), whole exome (WES), and clinical exome (CES) sequencing) in newborns admitted to neonatal intensive care units (NICUs) with suspected genetic disorders revealed a comparable median diagnostic rate (37.2%), but a higher median diagnostic turnaround time (22.3 days) than that obtained with NeoSeq. Our phenotype-driven gene panel, which is specific for genetic diseases in critically ill newborns is an affordable alternative to WGS and WES that offers comparable diagnostic efficacy, supporting its implementation as a first-tier genetic test in NICUs

Novel CYP4F22 mutations associated with autosomal recessive congenital ichthyosis (ARCI). Study of the CYP4F22 c.1303C>T founder mutation

Mutations in CYP4F22 cause autosomal recessive congenital ichthyosis (ARCI). However, less than 10% of all ARCI patients carry a mutation in CYP4F22. In order to identify the molecular basis of ARCI among our patients (a cohort of ninety-two Spanish individuals) we performed a mutational analysis using direct Sanger sequencing in combination with a multigene targeted NGS panel. From these, eight ARCI families (three of them with Moroccan origin) were found to carry five different CYP4F22 mutations, of which two were novel. Computational analysis showed that the mutations found were present in highly conserved residues of the protein and may affect its structure and function. Seven of the eight families were carriers of a highly recurrent CYP4F22 variant, c.1303C>T; p.(His435Tyr). A 12Mb haplotype was reconstructed in all c.1303C>T carriers by genotyping ten microsatellite markers flanking the CYP4F22 gene. A prevalent 2.52Mb haplotype was observed among Spanish carrier patients suggesting a recent common ancestor. A smaller core haplotype of 1.2Mb was shared by Spanish and Moroccan families. Different approaches were applied to estimate the time to the most recent common ancestor (TMRCA) of carrier patients with Spanish origin. The age of the mutation was calculated by using DMLE and BDMC2. The algorithms estimated that the c.1303C>T variant arose approximately 2925 to 4925 years ago, while Spanish carrier families derived from a common ancestor who lived in the XIII century. The present study reports five CYP4F22 mutations, two of them novel, increasing the number of CYP4F22 mutations currently listed. Additionally, our results suggest that the recurrent c.1303C>T change has a founder effect in Spanish population and c.1303C>T carrier families originated from a single ancestor with probable African ancestry