Sexual Dysfunction in Men Receiving Methadone Maintenance Treatment: Clinical History and Psychobiological Correlates

A variety of studies evidenced a relationship between drug use disorders and sexual dysfunction. In particular, heroin and opioid agonist medications to treat heroin dependence have been found to be associated with erectile dysfunction and reduced libido. Controversial findings also indicate the possibility of factors other than the pharmacological effects of opioid drugs concurring to sexual dysfunction. With the present study, we investigated the link between sexual dysfunction and long-term exposure to opioid receptor stimulation (heroin dependence, methadone maintenance treatment, methadone dosage), the potentially related hormonal changes reflecting hypothalamus-pituitarygonadal axis function and prolactin (PRL) pituitary release, the role of adverse childhood experiences in the clinical history and the concomitant symptoms of comorbid mental health disorders in contributing to sexual problems. Forty male patients participating in a long-term methadone treatment program were included in the present study and compared with 40 healthy control subjects who never used drugs nor abused alcohol. All patients and controls were submitted to the Arizona Sexual Experiences Scale (ASEX), Child Experiences of Care and Abuse-Questionnaire (CECA-Q) and the Symptom Check List-90 Scale. A blood sample for testosterone and PRL assays was collected. Methadone dosages were recorded among heroin-dependent patients on maintenance treatment. Methadone patients scored significantly higher than controls on the 5-item rating ASEX scale, on CECA-Q and on Symptoms Check List 90 (SCL 90) scale. Testosterone plasma levels were significantly lower and PRL levels significantly higher in methadone patients with respect to the healthy control group. ASEX scores reflecting sexual dysfunction were directly and significantly correlated with CECA-Q neglect scores and SCL 90 psychiatric symptoms total score. The linear regression model, when applied only to addicted patients, showed that methadone dosages were not significantly correlated with sexual dysfunction scores except for 'erectile dysfunction', for which an inverse association was evidenced. Testosterone values showed a significant inverse correlation with ASEX sexual dysfunction scores, CECA-Q neglect scores and psychiatric symptom at SCL 90 among methadone patients. PRL levels were directly and significantly correlated with sexual dysfunction scores, psychiatric symptoms at SCL 90 and CECA-Q neglect scores. Both testosterone and PRL did not correlate with methadone dosages. The present findings appear to support the view of childhood adversities and comorbid psychiatric symptoms contributing to sexual dysfunction and related hormonal changes among methadone patients, challenging the assumption that attributes sexual problems entirely to the direct pharmacological effects of opioid agonist medications

Dna methylation changes in fibromyalgia suggest the role of the immune‐inflammatory response and central sensitization

Fibromyalgia (FM) has been explained as a result of gene‐environment interactions. The present study aims to verify DNA methylation differences in eleven candidate genome regions previously associated to FM, evaluating DNA methylation patterns as potential disease biomarkers. DNA methylation was analyzed through bisulfite sequencing, comparing 42 FM women and their 42 healthy sisters. The associations between the level of methylation in these regions were further explored through a network analysis. Lastly, a logistic regression model investigated the regions potentially associated with FM, when controlling for sociodemographic variables and depressive symptoms. The analysis highlighted significant differences in the GCSAML region methylation between patients and controls. Moreover, seventeen single CpGs, belonging to other genes, were significantly different, however, only one cytosine related to GCSAML survived the correction for multiple comparisons. The network structure of methylation sites was different for each group; GRM2 methylation represented a central node only for FM patients. Logistic regression revealed that depressive symptoms and DNA methylation in the GRM2 region were significantly associated with FM risk. Our study encourages better exploration of GCSAML and GRM2 functions and their possible role in FM affecting immune, inflammatory response, and central sensitization of pain

By-products from winemaking and olive mill value chains for the enrichment of refined olive oil: Technological challenges and nutraceutical features

A growing body of literature is available about the valorization of food by-products to produce functional foods that combine the basic nutritional impact with the improvement of the health status of consumers. In this context, this study had two main objectives: (i) An innovative multistep extraction process for the production of a refined olive oil enriched with phenolic compounds (PE-ROO) extracted from olive pomace, olive leaves, or grape marc was presented and discussed. (ii) The most promising PE-ROOs were selected and utilized in in vitro and in vivo trials in order to determine their effectiveness in the management of high fat diet-induced-metabolic syndrome and oxidative stress in rats. The best results were obtained when olive leaves were used as source of phenols, regardless of the chemical composition of the solvent utilized for the extraction. Furthermore, while ethanol/hexane mixture was confirmed as a good solvent for the extraction of phenols compounds soluble in oil, the mix ROO/ethanol also showed a good extracting power from olive leaves. Besides, the ROO enriched with phenols extracted from olive leaves revealed an interesting beneficial effect to counteract high fat diet-induced-metabolic disorder and oxidative stress in rats, closely followed by ROO enriched by utilizing grape marc

Comparison between Ischemic and Hemorrhagic Strokes in Functional Outcome at Discharge from an Intensive Rehabilitation Hospital

Comparison studies on recovery outcomes in ischemic (IS) and hemorrhagic strokes (HS) have yielded mixed results. In this retrospective observational study of consecutive IS and HS patients, we aimed at evaluating functional outcomes at discharge from an intensive rehabilitation hospital, comparing IS vs. HS, analyzing possible predictors. Modified Rankin Scale (mRS) at discharge was the main outcome. Out of the 229 patients included (mean age 72.9 ± 13.9 years, 48% males), 81 had HS (35%). Compared with IS (n = 148), HS patients were significantly younger (75 ± 12.5 vs. 68.8 ± 15.4 years, p = 0.002), required longer hospitalizations both in acute (23.9 ± 36.7 vs. 35.2 ± 29.9 days, p = 0.019) and rehabilitation hospitals (41.5 ± 31.8 vs. 77.2 ± 51.6 days, p = 0.001), and had more severe initial clinical deficit (mean number of neurological impairments: 2.0 ± 1.1 vs. 2.6 ± 1.4, p = 0.001) and mRS scores at admission (p = 0.046). At discharge, functional status change, expressed as mRS, was not significantly different between IS and HS (F = 0.01, p = 0.902), nor was the discharge destination (p = 0.428). Age and clinical severity were predictors of functional outcome in both stroke types. On admission in an intensive rehabilitation hospital, HS patients presented a worse functional and clinical status compared to IS. Despite this initial gap, the two stroke types showed an overlapped trajectory of functional recovery, with age and initial stroke severity as the main prognostic factors

Prognostic impact of progression to induction chemotherapy and prior paclitaxel therapy in patients with germ cell tumors receiving salvage high-dose chemotherapy in the last 10 years: A study of the European Society for Blood and Marrow Transplantation Solid Tumors Working Party

Little is known about the prognostic impact of prior paclitaxel therapy and response to induction chemotherapy defined as the regimen preceding high-dose chemotherapy (HDCT) for the salvage therapy of advanced germ cell tumors. Twenty European Society for Blood and Marrow Transplantation centers contributed data on patients treated between 2002 and 2012. Paclitaxel used in either prior lines of therapy or in induction-mobilization regimens was considered. Multivariable Cox analyses of prespecified factors were undertaken on PFS and overall survival (OS). As of October 2013, data for 324 patients had been contributed to this study. One hundred and ninety-two patients (59.3%) had received paclitaxel. Sixty-one patients (19%) had a progression to induction chemotherapy, 234 (72%) a response (29 (9%) missing or granulocyte colony-stimulating factor without chemotherapy). Both progression to induction chemotherapy and prior paclitaxel were significantly associated with shorter OS univariably (P<0.001 and P=0.032). On multivariable analysis from the model with fully available data (N=216) progression to induction was significantly prognostic for PFS and OS (P=0.003), but prior paclitaxel was not (P=0.674 and P=0.739). These results were confirmed after multiple imputation of missing data. Progression to induction chemotherapy could be demonstrated as an independent prognostic factor, in contrast to prior paclitaxel

The role of the EP receptors for prostaglandin E2 in skin and skin cancer

One of the most common features of exposure of skin to ultraviolet (UV) light is the induction of inflammation, a contributor to tumorigenesis, which is characterized by the synthesis of cytokines, growth factors and arachidonic acid metabolites, including the prostaglandins (PGs). Studies on the role of the PGs in non-melanoma skin cancer (NMSC) have shown that the cyclooxygenase-2 (COX-2) isoform of the cyclooxygenases is responsible for the majority of the pathological effects of PGE2. In mouse skin models, COX-2 deficiency significantly protects against chemical carcinogen- or UV-induced NMSC while overexpression confers endogenous tumor promoting activity. Current studies are focused on identifying which of the G protein-coupled EP receptors mediate the tumor promotion/progression activities of PGE2 and the signaling pathways involved. As reviewed here, the EP1, EP2, and EP4 receptors, but not the EP3 receptor, contribute to NMSC development, albeit through different signaling pathways and with somewhat different outcomes. The signaling pathways activated by the specific EP receptors are context specific and likely depend on the level of PGE2 synthesis, the differential levels of expression of the different EP receptors, as well as the levels of expression of other interacting receptors. Understanding the role and mechanisms of action of the EP receptors potentially offers new targets for the prevention or therapy of NMSCs

Atazanavir and darunavir in pregnant women with HIV: Evaluation of laboratory and clinical outcomes from an observational national study

Background: Atazanavir and darunavir represent the main HIV PIs recommended in pregnancy, but comparativedata in pregnant women are limited.We assessed the safety and activity profile of these two drugs in pregnancyusing data from a national observational study.Methods: Women with atazanavir or darunavir exposure in pregnancy were evaluated for laboratory measuresand main pregnancy outcomes (e.g. preterm delivery, low birthweight, non-elective caesarean section and neonatalgestational age-adjusted birthweight Z-score).Results: Final analysis included 500 pregnancies with either atazanavir (n"409) or darunavir (n"91) exposure.No differences in pregnancy outcomes, weight gain in pregnancy, drug discontinuations, undetectable HIV-RNA,haemoglobin, ALT, total cholesterol, HDL cholesterol and LDL cholesterol were observed between the twogroups. At third trimester, exposure to darunavir was associated with higher levels of plasma triglycerides(median 235.5 versus 179 mg/dL; P"0.032) and a higher total cholesterol/HDL cholesterol ratio (median 4.03versus 3.27; P"0.028) and exposure to atazanavir was associated with higher levels of plasma bilirubin (1.54versus 0.32 mg/dL; P<0.001).Conclusions: In this observational study, the two main HIV PIs currently recommended by perinatal guidelinesshowed similar safety and activity in pregnancy, with no evidence of differences between the two drugs in termsof main pregnancy outcomes. Based on the minor differences observed in laboratory measures, prescribingphysicians might prefer either drug in some particular situations where the different impacts of treatment onlipid profile and bilirubin may have clinical relevance

Modeling Signal Propagation Mechanisms and Ligand-Based Conformational Dynamics of the Hsp90 Molecular Chaperone Full-Length Dimer

Hsp90 is a molecular chaperone essential for protein folding and activation in normal homeostasis and stress response. ATP binding and hydrolysis facilitate Hsp90 conformational changes required for client activation. Hsp90 plays an important role in disease states, particularly in cancer, where chaperoning of the mutated and overexpressed oncoproteins is important for function. Recent studies have illuminated mechanisms related to the chaperone function. However, an atomic resolution view of Hsp90 conformational dynamics, determined by the presence of different binding partners, is critical to define communication pathways between remote residues in different domains intimately affecting the chaperone cycle. Here, we present a computational analysis of signal propagation and long-range communication pathways in Hsp90. We carried out molecular dynamics simulations of the full-length Hsp90 dimer, combined with essential dynamics, correlation analysis, and a signal propagation model. All-atom MD simulations with timescales of 70 ns have been performed for complexes with the natural substrates ATP and ADP and for the unliganded dimer. We elucidate the mechanisms of signal propagation and determine “hot spots” involved in interdomain communication pathways from the nucleotide-binding site to the C-terminal domain interface. A comprehensive computational analysis of the Hsp90 communication pathways and dynamics at atomic resolution has revealed the role of the nucleotide in effecting conformational changes, elucidating the mechanisms of signal propagation. Functionally important residues and secondary structure elements emerge as effective mediators of communication between the nucleotide-binding site and the C-terminal interface. Furthermore, we show that specific interdomain signal propagation pathways may be activated as a function of the ligand. Our results support a “conformational selection model” of the Hsp90 mechanism, whereby the protein may exist in a dynamic equilibrium between different conformational states available on the energy landscape and binding of a specific partner can bias the equilibrium toward functionally relevant complexes

Thrombospondins in the heart: potential functions in cardiac remodeling

Cardiac remodeling after myocardial injury involves inflammation, angiogenesis, left ventricular hypertrophy and matrix remodeling. Thrombospondins (TSPs) belong to the group of matricellular proteins, which are non-structural extracellular matrix proteins that modulate cell–matrix interactions and cell function in injured tissues or tumors. They interact with different matrix and membrane-bound proteins due to their diverse functional domains. That the expression of TSPs strongly increases during cardiac stress or injury indicates an important role for them during cardiac remodeling. Recently, the protective properties of TSP expression against heart failure have been acknowledged. The current review will focus on the biological role of TSPs in the ischemic and hypertensive heart, and will describe the functional consequences of TSP polymorphisms in cardiac disease