Pathobiology of Lomentospora prolificans: could this species serve as a model of primary antifungal resistance?

The number of fungal isolates resistant to antifungal drugs has increased dramatically over the last few years and has become an important concern for clinicians. Among these isolates, fungi showing multidrug resistance are particularly worrying because of the difficulties associated with their treatment. These factors hamper the successful recovery of patients and drastically raise mortality rates. Antifungal resistance is multifactorial and several mechanisms in different fungi have been described. There is a need to study these mechanisms in depth; however, the study of antifungal drug resistance separately for each individual species makes progress in the field very slow and tedious. The selection of a multiresistant microorganism as a model for understanding resistance mechanisms and extrapolating the results to other species could help in the search for a solution. In this mini-review, we describe the pathobiology of Lomentospora (Scedosporium) prolificans, paying special attention to its intrinsic resistance to all currently available antifungal agents. The characteristics of L. prolificans offer several advantages: the possibility of using a single microorganism for the study of resistance to different drugs, even cases of double and triple resistance; it is biologically safe for society in general as no new genetically–modified strains are needed for the experiments; it is homologous with other fungal species, and there is repetitiveness between different strains. In conclusion, we propose L. prolificans as a candidate for consideration as a fungal model for the study of resistance mechanisms against antifungal agents.     

Transcatheter mitral valve repair in nonagenarians

Given the increase in life expectancy indeveloped countries,nonagenarian population will become clinically and numerically relevant in our daily routine practice in the near future.Age has been observed to exert a profound influence on the prevalence of severe mitral regurgitation (MR) in the population.[1]Mitral valve surgery remains the gold standard of care for patients with symptomatic severe MR.     

Exogenous hormone use and cutaneous melanoma risk in women: The European Prospective Investigation into Cancer and Nutrition

Evidence suggests an influence of sex hormones on cutaneous melanoma risk, but epidemiologic findings are conflicting. We examined the associations between use of oral contraceptives (OCs) and menopausal hormone therapy (MHT) and melanoma risk in women participating in the European Prospective Investigation into Cancer and Nutrition (EPIC). EPIC is a prospective cohort study initiated in 1992 in 10 European countries. Information on exogenous hormone use at baseline was derived from country-specific self-administered questionnaires. We used Cox proportional hazards regression models to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). Over 1992–2015, 1,696 melanoma cases were identified among 334,483 women, whereof 770 cases among 134,758 postmenopausal women. There was a positive, borderline-significant association between OC use and melanoma risk (HR = 1.12, 95% CI = 1.00–1.26), with no detected heterogeneity across countries (p_homogeneity = 0.42). This risk increased linearly with duration of use (p_trend = 0.01). Among postmenopausal women, ever use of MHT was associated with a nonsignificant increase in melanoma risk overall (HR = 1.14, 95% CI = 0.97–1.43), which was heterogeneous across countries (p_homogeneity = 0.05). Our findings do not support a strong and direct association between exogenous hormone use and melanoma risk. In order to better understand these relations, further research should be performed using prospectively collected data including detailed information on types of hormone, and on sun exposure, which may act as an important confounder or effect modifier on these relations.     

'In vitro' binding of propofol to serum lipoproteins in thyroid dysfunction

OBJECTIVE: To determine a regression relationship between the unbound fraction (fu percent) of propofol, a highly lipophilic intravenous anaesthetic agent, and demographic and biochemical variables in a thyroid dysfunction population. METHODS: Serum samples from patients with hypo- (n=33) and hyperthyroidism (n=33) and also from healthy volunteers (control group; n=9) were spiked with propofol to a total (bound + unbound propofol) concentration of 10 microg/ml. The unbound concentration was determined using ultrafiltration followed by high-performance liquid chromatography with fluorimetric detection and the unbound fraction percent (fu) and the binding ratio [bound/free concentration (B/F)] were calculated. Albumin, alpha(1)-acid glycoprotein, cholesterol, triglycerides, HDL, LDL, VLDL lipoproteins, and T3 and T4 hormone concentrations were measured. B/F has a linear relationship with lipoprotein concentration--unlike that for fu which is curvilinear - so, we developed a linear regression model of B/F for propofol with the above biochemical variables and with gender. RESULTS: The fu in hypothyroidism was significantly lower than in the healthy control (mean +/- standard deviation 0.74 +/- 0.13% vs 0.87 +/- 0.12%, P < 0.01) but the fu was no different in hyperthyroid subjects than controls (0.94 +/- 0.16% vs 0.87 +/- 0.12%, P > 0.05). HDL, LDL and VLDL lipoproteins were significant predictors of B/F (P < 0.05) and were capable of explaining 54% of the variability in the 'in vitro' binding of propofol in thyroid disease. CONCLUSION: These results could help explain the interindividual variability in the protein binding of propofol in thyroid dysfunction patients and suggest the inclusion of lipoproteins in covariate model development for the pharmacokinetic/pharmacodynamic parameters of propofol.     

Neuroprotection by the cannabinoid agonist WIN-55212 in an in vivo newborn rat model of acute severe asphyxia

This study was designed to evaluate the neuroprotective effect of the cannabinoid agonist WIN-55212 after inducing acute severe asphyxia in newborn rats. The left common carotid artery was ligated in anaesthetised 7-day-old Wistar rats, which were then asphyxiated by inhaling 100% nitrogen for 10 min. Pups recovering from asphyxia were s.c. administered vehicle (n=23), WIN-55212 (0.1 mg/kg, n=18), or WIN-55212 plus the CB1 receptor antagonist SR141716 (3 mg/kg, n=10). Pups undergoing a sham operation served as controls (n=12). Coronal sections of the brain were obtained on the 14th day after surgery and observed under light microscope after Nissl or Fluoro-Jade B (FJB) staining, to respectively quantify surviving or degenerating neurones in the CA1 area of the hippocampus and parietal cortex. Acute asphyxia led to early neurone loss amounting to 19% in the hippocampus and 29% in the cortex (both ANOVA P<0.05 vs. control). Delayed neurone loss occurred in the proportions 13% in the hippocampus and 20% in the cortex (both ANOVA P<0.05 vs. control). Neuronal loss was fully prevented by WIN-55212 administration. Co-administration of SR141716 failed to modify the protective effect of WIN-55212 on early neuronal death, but abolished the WIN-55212-induced prevention of delayed neuronal death. We conclude that when administered after acute severe asphyxia in newborn rats, WIN-55212 shows a neuroprotective effect, reducing both early and delayed neurone loss. This effect is achieved through two parallel CB1-dependent and -independent mechanisms.     

Experimental Swine Lung Autotransplant Model to Study Lung Ischemia–Reperfusion Injury

IntroductionIschemia–reperfusion (IR) lung injury has been investigated extensively on clinical and experimental models of cold ischemia. However, relatively few studies examine the detailed biochemical changes occurring during normothermic (warm) IR.Animals and methodsSix large-white pigs underwent a lung autotransplant which entailed left pneumonectomy, ex situ cranial lobectomy, caudal lobe reimplantation and its reperfusion for 30 min. Throughout the procedure, several parameters were measured in order to identify hemodynamic, gasometric and biochemical changes. Non-parametric statistical analyses were used to compare differences between periods.ResultsAfter ischemia, a significant increase (p < .05) in lipid peroxidation metabolites, proinflammatory cytokines and chemokines (TNF-α, IL-1β and MCP-1), neutrophil activation, inducible nitric oxide synthase activity and protein kinase MAPK p38 levels were observed in lung tissue. However, constitutive nitric oxide synthase activity in lung tissue and carbon monoxide plasma levels decreased. The same held true throughout the reperfusion period, when an increase in the constitutive heme-oxygenase activity was also shown.ConclusionsAn experimental model of normothermic lung IR injury is presented and detailed changes in hemodynamic, gasometric and biochemical parameters are shown. Both the model and the studied parameters may be clinically useful in future investigations testing new therapies to prevent normothermic IR induced lung injury.     

Steroid-refractory ulcerative colitis and associated primary sclerosing cholangitis treated with infliximab

Primary sclerosing cholangitis is an infrequent extraintestinal manifestation of ulcerative colitis.Damage to bile ducts is irreversible and medical therapies to prevent progression of the disease are usually ineffective.We describe a patient with long-standing ulcerative colitis,which was refractory to corticosteroid therapy who developed primary sclerosing cholangitis(biochemical stage Ⅱ/Ⅳ) in the course of his pancolitis.Treatment with infliximab(5 mg/kg as an induction dose followed by maintenance doses every two months) was indicated because of steroid-dependent disease associated to primary sclerosing cholangitis as well as sacroiliitis and uveitis and previous episode of severe azathioprinerelated hepatic toxicity.At present,after two years of follow-up,the patient is asymptomatic with normal liver tests and complete resumption of daily life activities.This case draws attention to the usefulness of antitumor necrosis factor-alpha therapy for the management of primary sclerosing cholangitis as extraintestinal manifestation of inflammatory bowel disease.