Absence of Hepatitis E virus circulation in wild rabbits (Oryctolagus cuniculus) and Iberian hares (Lepus granatensis) in Mediterranean ecosystems in Spain

In recent decades, cases of autochthonous hepatitis E (HE) have sharply increased in European countries where foodborne transmission is considered the main route of HE virus (HEV) transmission. Although rabbits are considered the main reservoir of the zoonotic HEV‐3ra subtype, information on the role of wild lagomorphs in the epidemiology of HEV remains scarce. The aim of this study therefore was to assess the circulation of HEV in European wild rabbits (Oryctolagus cuniculus) and Iberian hares (Lepus granatensis), the most important lagomorph species in Spanish Mediterranean ecosystems. Liver samples from 372 wild rabbits and 78 Iberian hares were analysed using a broad‐spectrum RT‐PCR that detects HEV genotypes 1–8. None of the 450 lagomorphs tested were positive for HEV infection. To the best of our knowledge, this is the first study to assess HEV circulation in wild rabbits in Spain and the first to evaluate HEV infection in Iberian hares. Our results indicate absence of HEV circulation in wild rabbits and Iberian hares in southern Spain during the study period, which suggests that the risk of transmission of HEV from wild lagomorphs to other species, including humans, is low.     

Rotator Cuff Tear Susceptibility Is Associated With Variants in Genes Involved in Tendon Extracellular Matrix Homeostasis

Rotator cuff tears (RCT) is a multifactorial disease with genetic factors contributing for the disease etiology. We hypothesized that genetic variants in genes involved in extracellular matrix (ECM) homeostasis may alter susceptibility to RCT. We evaluated 20 polymorphisms of genes involved in ECM homeostasis in 211 cases of full-thickness tears of the supraspinatus (N_females = 130; N_males = 81) and 567 age-matched controls (N_females = 317; N_males = 250). Multivariate logistic regressions were carried out with age, gender, genetic ancestry (based on the analysis of 61 biallelic short insertion/deletion polymorphisms), and common co-morbidities (diabetes, dyslipidemia, and smoking habits) as covariates. We observed that carriers of the rare allele of both studied variants of TGFB1, as well as their G/A (rs1800470/rs1800469) haplotype, were less susceptible to RCT (p < 0.05). In contrast, carriers of the G allele of MMP9 rs17576 (p = 0.014) or G/G haplotype (rs17576/rs17577; p < 0.001) had an increased risk for tendon tears. The presence of the T allele of MMP2 rs2285053 (p = 0.033), the T allele of MMP3 rs679620 (p = 0.024), and the TT-genotype of TIMP2 rs2277698 (p = 0.01) was associated with susceptibility to tears, especially in females. In males, the A allele of COL5A1 rs3196378 (p = 0.032) and the G allele of TGFBR1 rs1590 (p = 0.039) were independent risk factors for RCT. The C/T COL5A1 (rs3196378/rs11103544) haplotype was associated with a reduced risk of tears in males (p = 0.03). In conclusion, we identified the genetic variants associated with RCT susceptibility, thereby reinforcing the role of genes involved in the structure and homeostasis of the ECM of tendons in disease development. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 38:192–201, 2020     

Small-molecule XIAP inhibitors derepress downstream effector caspases and induce apoptosis of acute myeloid leukemia cells

We tested the effects of small-molecule XIAP antagonists based on a polyphenylurea pharmacophore on cultured acute myelogenous leukemia (AML) cell lines and primary patient samples. X-linked inhibitor of apoptosis protein (XIAP) antagonist N-[(5R)-6-[(anilinocarbonyl)amino]-5-((anilinocarbonyl){[(2R)-1-(4-cyclohexylbutyl)pyrrolidin-2-yl]methyl}amino)hexyl]-N-methyl-N'-phenylurea (1396-12), but not a structurally related control compound, induced apoptosis of primary leukemia samples with a lethal dose (LD50) of less than 10 microM in 16 of 27 (60%) samples. In contrast, XIAP antagonist 1396-12 was not lethal to the normal hematopoietic cells in short-term cytotoxicity assays. Response of primary AML specimens to XIAP inhibitor correlated with XIAP protein levels, with higher levels of XIAP associated with sensitivity. The XIAP antagonist 1396-12 induced activation of downstream caspases 3 and 7 prior to the activation of upstream caspase 8 and caspase 9. Apoptosis induction was also independent of B-cell lymphoma protein-2 (Bcl-2) or caspase 8, indicative of a downstream effect on apoptotic pathways. Thus, polyphenylurea-based XIAP antagonsists directly induce apoptosis of leukemia cells and AML patient samples at low micromolar concentrations through a mechanism of action distinct from conventional chemotherapeutic agents.     

Clinical characteristics and prognostic factors of sinonasal undifferentiated carcinoma: a multicenter study

Background

Sinonasal undifferentiated carcinoma (SNUC) is a very rare entity with a poor prognosis. Due to the lack of studies on the subject, evidence is lacking concerning its management.

Methods

A multicenter collaborative study was conducted to assess treatment strategy, oncological outcome, and prognostic factors.

Results

Definitive analyses focused on 54 patients with a majority of advanced stage; the 3‐year overall survival (OS) and 3‐year recurrence‐free survival (RFS) rates were, respectively, 62.4% and 47.8%. During the follow‐up, 18 patients (33.3%) died, 10 (18.5%) developed metastases, 7 had lymph‐node involvement (13%), and 12 (22.2%) showed recurrence or local progression. In univariate analyses, treatment modalities associated with improved RFS were induction chemotherapy (p = 0.02) and intensity‐modulated radiotherapy (p = 0.007). In the multivariate analyses, only induction chemotherapy (p = 0.047, hazard ratio [HR] = 0.39) was significantly associated with improved RFS.

Conclusion

Multimodal therapies including induction chemotherapy and intensity‐modulated radiotherapy may improve the prognosis of SNUC; surgery might improve local control. Further multicenter studies are required.

     

Melatonin and viral infections

The therapeutic effects of melatonin against viral infections, with emphasis on the Venezuelan equine encephalomyelitis (VEE), are reviewed. Melatonin has been shown to prevent paralysis and death in mice infected with the encephalomyocarditis virus and to decrease viremia. Melatonin also postpones the onset of the disease produced by Semliki Forest virus inoculation and reduces the mortality of West Nile virus-infected mice stressed by either isolation or dexamethasone injection. An increase in the host resistance to the virus via a peripheral immunostimulatory activity is considered responsible for these effects. It has also been demonstrated that melatonin protects some strains of mink against Aleutian disease, and prevents the reduction of B- and T-cells as well as Th1 cytokine secretion in mice infected with leukemia retrovirus. In VEE-infected mice, melatonin postpones the onset of the disease and death for several days and reduces the mortality rate. This protective effect seems to be due to the increase in the production of interleukin-1beta (IL-1beta), as 100% of the infected mice treated with melatonin die when IL-1beta is blocked with antimurine IL-1beta antibodies. Although melatonin administration raises serum levels of tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma), the mortality observed in neutralization experiments with the corresponding anticytokine antibodies, suggests that neither TNF-alpha nor IFN-gamma are essential for the protective effect of melatonin on murine VEE virus infection. Melatonin treatment also enhances the efficiency of immunization against the VEE virus. Reactive oxygen species have been implicated in the dissemination of this virus, and their deleterious effects may be diminished by melatonin. This indole inhibits nitric oxide synthetase activity and it is a potent scavenger of nitric oxide, which also plays an important role in the spread of the VEE virus. In conclusion, the immunomodulatory, antioxidant, and neuroprotective effects of melatonin suggest that this indole must be considered as an additional therapeutic alternative to fight viral diseases.     

Detection of carbapenemases and other mechanisms of enzymatic resistance to β-lactams in Enterobacteriaceae with diminished susceptibility to carbapenems in a tertiary care hospital

Introduction

Our objective was to characterize the enzymatic β-lactam resistance in clinical Enterobacteriaceae isolates with diminished susceptibility to carbapenems from 2013 to 2014 at Hospital Universitario Miguel Servet.

Secretion of LH in spontaneously hypertensive rats

Weights of testes, seminal vesicles, ventral prostate and pituitary, plasma testosterone and LH concentrations, pituitary LH content and concentration, the LH in-vivo response after LHRH administration (1 microgram), and basal and LHRH-stimulated secretion in vitro were analysed in adult male spontaneously hypertensive (SH) and normotensive control (WKY) rats. Spontaneously hypertensive rats showed: testis and pituitary hypertrophy; seminal vesicle and ventral prostate atrophy; increased plasma testosterone and LH concentrations; increased pituitary LH content and concentration; unchanged net increase of plasma concentrations of LH 15 and 45 min after administration of 1 microgram LHRH; and increased basal LH secretion in vitro with a normal response to LHRH stimulation. These results provide evidence that SH rats show increased LH secretion with a normal response to LHRH stimulation. The coexistence of high plasma concentrations of testosterone with seminal vesicle and ventral prostate atrophy suggest a reduction in the effectiveness of testosterone in these structures.     

A Disrupted-in-Schizophrenia 1 Gene Variant is Associated with Clinical Symptomatology in Patients with First-Episode Psychosis

Objective

DISC1 gene is one of the main candidate genes for schizophrenia since it has been associated to the illness in several populations. Moreover, variations in several DISC1 polymorphisms, and in particular Ser704Cys SNP, have been associated in schizophrenic patients to structural and functional modifications in two brain areas (pre-frontal cortex and hippocampus) that play a central role in the genesis of psychotic symptoms. This study tested the association between Ser704Cys DISC1 polymorphism and the clinical onset of psychosis.

Methods

Two hundred and thirteen Caucasian drug-naive patients experiencing a first episode of non-affective psychosis were genotyped for rs821616 (Ser704Cys) SNP of the DISC1 gene. The clinical severity of the illness was assessed using SAPS and SANS scales. Other clinical and socio-demographic variables were recorded to rule out possible confounding effects.

Results

Patients homozygous for the Ser allele of the Ser704Cys DISC1 SNP had significantly (p<0.05) higher rates at the positive symptoms dimension (SAPS-SANS scales) and hallucinations item, compared to Cys carriers.

Conclusion

DISC1 gene variations may modulate the clinical severity of the psychosis at the onset of the disorder.     

Global estimates of undiagnosed diabetes in adults

Aims

The prevalence of diabetes is rapidly increasing worldwide. Type 2 diabetes may remain undetected for many years, leading to severe complications and healthcare costs. This paper provides estimates of the prevalence of undiagnosed diabetes mellitus (UDM), using available data from high quality representative population-based sources.

Methods

Data sources reporting both diagnosed and previously undiagnosed diabetes were identified and selected according to previously described IDF methodology for diabetes in adults (aged 20–79). Countries were divided into 15 data regions based on their geographic IDF Region and World Bank income classification. The median UDM proportion was calculated from selected data sources for each of data region. The number of UDM cases in 2013 was calculated from country, age and sex-specific estimates of known diabetes cases and data region-specific UDM proportion.

Results

Of 744 reviewed data sources, 88 sources representing 74 countries had sufficient information and were selected for generation of estimates of UDM. Globally, 45.8%, or 174.8 million of all diabetes cases in adults are estimated to be undiagnosed, ranging from 24.1% to 75.1% across data regions. An estimated 83.8% of all cases of UDM are in low- and middle-income countries. At a country level, Pacific Island nations have the highest prevalence of UDM.

Conclusions

There is a high proportion of UDM globally, and especially in developing countries. Further high-quality studies of UDM are needed to strengthen future estimates.