Pattern dystrophy with high intrafamilial variability associated with Y141C mutation in the peripherin/RDS gene and successful treatment of subfoveal CNV related to multifocal pattern type with anti-VEGF (ranibizumab) intravitreal injections.

OBJECTIVE: To identify disease causing mutation in three generations of a Swiss family with pattern dystrophy and high intrafamilial variability of phenotype. To assess the effect of intravitreal ranibizumab injections in the treatment of subfoveal choroidal neovascularization associated with pattern dystrophy in one patient. METHODS: Affected family members were ascertained for phenotypic and genotypic characterization. Ophthalmic evaluations included fundus photography, autofluorescence imaging, optical coherence tomography, and International Society for Clinical Electrophysiology of Vision standard full-field electroretinography. When possible family members had genetic testing. The proband presented with choroidal neovascularization and had intravitreal injections as needed according to visual acuity and optical coherence tomography. RESULTS: Proband had a multifocal type pattern dystrophy, and his choroidal neovascularization regressed after four intravitreal injections. The vision improved from 0.8 to 1.0, and optical coherence tomography showed complete anatomical restoration. A butterfly-shaped pattern was observed in her cousin, whereas a fundus pulverulentus pattern was seen in a second cousin. Aunt had a multifocal atrophic appearance, simulating geographic atrophy in age-related macular degeneration. The Y141C mutation was identified in the peripherin/RDS gene and segregated with disease in the family. CONCLUSION: This is the first report of marked intrafamilial variation of pattern dystrophy because of peripherin/RDS Y141C mutation. Intravitreal ranibizumab injections might be a valuable treatment for associated subfoveal choroidal neovascularization.

ADC mapping of chronic cerebral hypoperfusion induced by carotid artery stenosis.

BACKGROUND: Carotid artery stenosis is associated with the occurrence of acute and chronic ischemic lesions that increase with age in the elderly population. Diffusion Imaging and ADC mapping may be an appropriate method to investigate patients with chronic hypoperfusion consecutive to carotid stenosis. This non-invasive technique allows to investigate brain integrity and structure, in particular hypoperfusion induced by carotid stenosis diseases. The aim of this study was to evaluate the impact of a carotid stenosis on the parenchyma using ADC mapping. METHODS: Fifty-nine patients with symptomatic (33) and asymptomatic (26) carotid stenosis were recruited from our multidisciplinary consultation. Both groups demonstrated a similar degree of stenosis. All patients underwent MRI of the brain including diffusion-weighted MR imaging with ADC mapping. Regions of interest were defined in the anterior and posterior paraventricular regions both ipsilateral and contralateral to the stenosis (anterior circulation). The same analysis was performed for the thalamic and occipital regions (posterior circulation). RESULTS: ADC values of the affected vascular territory were significantly higher on the side of the stenosis in the periventricular anterior (P<0.001) and posterior (P<0.01) area. There was no difference between ipsilateral and contralateral ADC values in the thalamic and occipital regions. CONCLUSIONS: We have shown that carotid stenosis is associated with significantly higher ADC values in the anterior circulation, probably reflecting an impact of chronic hypoperfusion on the brain parenchyma in symptomatic and asymptomatic patients. This is consistent with previous data in the literature.

Poly (ADP-ribose) polymerase-1 is a key mediator of liver inflammation and fibrosis.

Poly (ADP-ribose) polymerase 1 (PARP-1) is a constitutive enzyme, the major isoform of the PARP family, which is involved in the regulation of DNA repair, cell death, metabolism, and inflammatory responses. Pharmacological inhibitors of PARP provide significant therapeutic benefits in various preclinical disease models associated with tissue injury and inflammation. However, our understanding the role of PARP activation in the pathophysiology of liver inflammation and fibrosis is limited. In this study we investigated the role of PARP-1 in liver inflammation and fibrosis using acute and chronic models of carbon tetrachloride (CCl4 )-induced liver injury and fibrosis, a model of bile duct ligation (BDL)-induced hepatic fibrosis in vivo, and isolated liver-derived cells ex vivo. Pharmacological inhibition of PARP with structurally distinct inhibitors or genetic deletion of PARP-1 markedly attenuated CCl4 -induced hepatocyte death, inflammation, and fibrosis. Interestingly, the chronic CCl4 -induced liver injury was also characterized by mitochondrial dysfunction and dysregulation of numerous genes involved in metabolism. Most of these pathological changes were attenuated by PARP inhibitors. PARP inhibition not only prevented CCl4 -induced chronic liver inflammation and fibrosis, but was also able to reverse these pathological processes. PARP inhibitors also attenuated the development of BDL-induced hepatic fibrosis in mice. In liver biopsies of subjects with alcoholic or hepatitis B-induced cirrhosis, increased nitrative stress and PARP activation was noted. CONCLUSION: The reactive oxygen/nitrogen species-PARP pathway plays a pathogenetic role in the development of liver inflammation, metabolism, and fibrosis. PARP inhibitors are currently in clinical trials for oncological indications, and the current results indicate that liver inflammation and liver fibrosis may be additional clinical indications where PARP inhibition may be of translational potential.

Is high dose rate brachytherapy reliable and effective treatment for prostate cancer patients? A review of the literature.

The intrinsic physical and radiobiological characteristics of High Dose Rate Brachytherapy (HDR-BT) are well suited to the treatment of prostate cancer. HDR-BT was initially used as a boost to external beam brachytherapy, but has subsequently been employed as the sole treatment, which is termed HDR monotherapy. This review summarizes the clinical outcomes and toxicity results of the principal studies and discusses the radiobiological basis supporting its use.

Role of CYP2E1-mediated metabolism in the acute and vestibular toxicities of nineteen nitriles in the mouse

Allylnitrile, cis-crotononitrile, and 3,3 -iminodipropionitrile are known to cause vestibular toxicity in rodents, and evidence is available indicating that cis-2-pentenenitrile shares this effect. We evaluated nineteen nitriles for vestibular toxicity in wild type (129S1) and CYP2E1-null mice, including all the above, several neurotoxic nitriles, and structurally similar nitriles. A new acute toxicity test protocol was developed to facilitate evaluation of the vestibular toxicity by a specific behavioral test battery at doses up to sub-lethal levels while using a limited number of animals. A mean number of 8.5±0.3 animals per nitrile, strain and sex was necessary to obtain evidence of vestibular toxicity and optionally an estimation of the lethal dose. For several but not all nitriles, lethal doses significantly increased in CYP2E1-null mice. The protocol revealed the vestibular toxicity of five nitriles, including previously identified ototoxic compounds and one nitrile (trans-crotononitrile) known to have a different profile of neurotoxic effects in the rat. In all five cases, both sexes were affected and no decrease in susceptibility was apparent in CYP2E1-null mice respect to 129S1 mice. Fourteen nitriles caused no vestibular toxicity, including six nitriles tested in CYP2E1-null mice at doses significantly larger than the maximal doses that can be tested in wild type animals. We conclude that only a subset of low molecular weight nitriles is toxic to the vestibular system, that species-dependent differences exist in this vestibular toxicity, and that CYP2E1-mediated metabolism is not involved in this effect of nitriles although it has a role in the acute lethality of some of these compounds

Central serous chorioretinopathy: Recent findings and new physiopathology hypothesis.

Central serous chorioretinopathy (CSCR) is a major cause of vision threat among middle-aged male individuals. Multimodal imaging led to the description of a wide range of CSCR manifestations, and highlighted the contribution of the choroid and pigment epithelium in CSCR pathogenesis. However, the exact molecular mechanisms of CSCR have remained uncertain. The aim of this review is to recapitulate the clinical understanding of CSCR, with an emphasis on the most recent findings on epidemiology, risk factors, clinical and imaging diagnosis, and treatments options. It also gives an overview of the novel mineralocorticoid pathway hypothesis, from animal data to clinical evidences of the biological efficacy of oral mineralocorticoid antagonists in acute and chronic CSCR patients. In rodents, activation of the mineralocorticoid pathway in ocular cells either by intravitreous injection of its specific ligand, aldosterone, or by over-expression of the receptor specifically in the vascular endothelium, induced ocular phenotypes carrying many features of acute CSCR. Molecular mechanisms include expression of the calcium-dependent potassium channel (KCa2.3) in the endothelium of choroidal vessels, inducing subsequent vasodilation. Inappropriate or over-activation of the mineralocorticoid receptor in ocular cells and other tissues (such as brain, vessels) could link CSCR with the known co-morbidities observed in CSCR patients, including hypertension, coronary disease and psychological stress.

Disease profiles of detainees in the Canton of Vaud in Switzerland: gender and age differences in substance abuse, mental health and chronic health conditions.

BACKGROUND: Literature on the disease profile of prisoners that differentiates by age and gender remains sparse. This study aimed to describe the health of correctional inmates in terms of substance abuse problems and mental and somatic health conditions, and compare it by gender and age. METHODS: This study examined cross-sectional data from the Canton of Vaud in Switzerland on the health conditions of detainees who were in prison on January 1, 2011 or entered prison in 2011. Health conditions validated by physician examination were reported using the International Classification of Diseases (ICD) version 10. The analyses were descriptive by groups of prisoners: the entire sample (All), Men, Older adults and Women. RESULTS: A total of 1,664 individuals were included in the analysis. Men comprised 91.5 % of the sample and had a mean age of 33 years. The other 8.5 % were women and had an average age of 39. Older adults (i.e., age 50 and older) represented 7 % of the total sample. Overall, 80 % of inmates were non-Swiss citizens, but the proportion of Swiss prisoners was higher among the older adults (51 %) and women (29 %). Overall, 41 % of inmates self-reported substance abuse problems. Of those, 27 % were being treated by psychiatrists for behavioral disorders related to substance abuse. Chronic infectious diseases were found in 9 % of the prison population. In addition, 27 % of detainees suffered from serious mental health conditions. Gender and age had an influence on the disease profile of this sample: compared to the entire prison population, the older inmates were less likely to misuse illegal drugs and to suffer from communicable infections but exhibited more problems with alcohol and a higher burden of chronic health conditions. Female prisoners were more disposed to mental health problems (including drug abuse) and infectious diseases. In terms of chronic diseases, women suffered from the same conditions as men, but the diseases were more prevalent in women. CONCLUSION: It is important to understand the different disease profiles of prisoners by gender and age, as it helps identify the needs of different groups and tailor age-and gender-specific interventions.

Mechanisms of Antifungal Drug Resistance.

Antifungal therapy is a central component of patient management for acute and chronic mycoses. Yet, treatment choices are restricted because of the sparse number of antifungal drug classes. Clinical management of fungal diseases is further compromised by the emergence of antifungal drug resistance, which eliminates available drug classes as treatment options. Once considered a rare occurrence, antifungal drug resistance is on the rise in many high-risk medical centers. Most concerning is the evolution of multidrug- resistant organisms refractory to several different classes of antifungal agents, especially among common Candida species. The mechanisms responsible are mostly shared by both resistant strains displaying inherently reduced susceptibility and those acquiring resistance during therapy. The molecular mechanisms include altered drug affinity and target abundance, reduced intracellular drug levels caused by efflux pumps, and formation of biofilms. New insights into genetic factors regulating these mechanisms, as well as cellular factors important for stress adaptation, provide a foundation to better understand the emergence of antifungal drug resistance.

High hepatic and extrahepatic mortality and low treatment uptake in HCV-coinfected persons in the Swiss HIV cohort study between 2001 and 2013.

BACKGROUND & AIMS: The landscape of HCV treatments is changing dramatically. At the beginning of this new era, we highlight the challenges for HCV therapy by assessing the long-term epidemiological trends in treatment uptake, efficacy and mortality among HIV/HCV-coinfected people since the availability of HCV therapy. METHODS: We included all SHCS participants with detectable HCV RNA between 2001 and 2013. To identify predictors for treatment uptake uni- and multivariable Poisson regression models were applied. We further used survival analyses with Kaplan-Meier curves and Cox regression with drop-out as competing risk. RESULTS: Of 12,401 participants 2107 (17%) were HCV RNA positive. Of those, 636 (30%) started treatment with an incidence of 5.8/100 person years (PY) (95% CI 5.3-6.2). Sustained virological response (SVR) with pegylated interferon/ribavirin was achieved in 50% of treated patients, representing 15% of all participants with replicating HCV-infection. 344 of 2107 (16%) HCV RNA positive persons died, 59% from extrahepatic causes. Mortality/100 PY was 2.9 (95% CI 2.6-3.2) in untreated patients, 1.3 (1.0-1.8) in those treated with failure, and 0.6 (0.4-1.0) in patients with SVR. In 2013, 869/2107 (41%) participants remained HCV RNA positive. CONCLUSIONS: Over the last 13years HCV treatment uptake was low and by the end of 2013, a large number of persons remain to be treated. Mortality was high, particularly in untreated patients, and mainly due to non-liver-related causes. Accordingly, in HIV/HCV-coinfected patients, integrative care including the diagnosis and therapy of somatic and psychiatric disorders is important to achieve mortality rates similar to HIV-monoinfected patients.

Do therapist behaviors differ with Hispanic youth? A brief look at within-session therapist behaviors and youth treatment response.

Brief addiction treatments, including motivational interviewing (MI), have shown promise with youth. One underexamined factor in this equation is the role of therapist behaviors. We therefore sought to assess whether and how therapist behaviors differ for Hispanic versus non-Hispanic youth and how that may be related to treatment outcome. With 80 substance-using adolescents (M age = 16 years; 65% male; 59% Hispanic; 41% non-Hispanic), we examined the relationship between youth ethnicity and therapist behaviors across two brief treatments (MI and alcohol/marijuana education [AME]). We then explored relationships to youth 3-month treatment response across four target outcomes: binge drinking days, alcohol-related problems, marijuana use days, and marijuana-related problems. In this study, therapists showed significantly more MI skills within the MI condition and more didactic skills in the AME condition. With respect to youth ethnicity, across both conditions (MI and AME), therapists used less MI skills with Hispanic youth. Contrary to expectations, therapists' use of MI skills was not connected to poorer outcomes for Hispanic youth across the board (e.g., for binge drinking days, marijuana use days, or marijuana-related problems). Rather, for Hispanic youth, therapists' use of lower MI skills was related only to poorer treatment outcomes in the context of alcohol-related problems. The observed relationships highlight the importance of investigating salient treatment interactions between therapist factors and youth ethnicity to guide improvements in youth treatment response. (PsycINFO Database Record

Proteomics and chronic inflammatory bowel diseases.

Inflammatory bowel diseases (IBD) are relatively frequent in developed countries. Physiopathological events involved in the etiology of IBDs include activation of immune, mesenchymal and epithelial cells. This review gives an overview of the currently applied proteomics technologies. It describes metabolic changes and goes into the approaches using this methodology to understand the molecular mechanisms implicated in the development of the disease.

Vestibular Schwannoma: The Evolution of Hearing and Tumor Size in Natural Course and after Treatment by LINAC Stereotactic Radiosurgery.

OBJECTIVE: To review the natural course of tumor size and hearing during conservative management of 151 patients with unilateral vestibular schwannoma (VS), and to evaluate the same parameters for the part of the group (n = 84) who were treated by LINAC stereotactic radiosurgery (SRS). METHODS: In prospectively collected data, patients underwent MRI and complete audiovestibular tests at inclusion, during the conservative management period and after SRS. Hearing was graded according to the Gardner-Robertson (GR) scale and tumor size according to Koos. Statistics were performed using Kaplan-Meier survival analysis and multivariate analyses including linear and logistic regression. Specific insight was given to patients with serviceable hearing. RESULTS: During the conservative management period (mean follow-up time: 24 months, range: 6-96), the annual risk of GR class degradation was 6% for GRI and 15% for GR II patients. Hearing loss as an initial symptom was highly predictive of further hearing loss (p = 0.003). Tumor growth reached 25%. For SRS patients, functional hearing preservation was 51% at 1 year and 36% at 3 years. Tumor control was 94 and 91%, respectively. CONCLUSION: In VS patients, hearing loss at the time of diagnosis is a predictor of poorer hearing outcome. LINAC SRS is efficient for tumor control. Patients who preserved their pretreatment hearing presented less hearing loss per year after SRS than before treatment, suggesting a protective effect of SRS when cochlear function can be preserved.

International comparison of the German evidence-based S3-guidelines on the diagnosis and multimodal treatment of early and locally advanced gastric cancer, including adenocarcinoma of the lower esophagus.

BACKGROUND: Clinical guidelines are essential in implementing and maintaining nationwide stage-specific diagnostic and therapeutic standards. In 2011, the first German expert consensus guideline defined the evidence for diagnosis and treatment of early and locally advanced esophagogastric cancers. Here, we compare this guideline with other national guidelines as well as current literature. METHODS: The German S3-guideline used an approved development process with de novo literature research, international guideline adaptation, or good clinical practice. Other recent evidence-based national guidelines and current references were compared with German recommendations. RESULTS: In the German S3 and other Western guidelines, adenocarcinomas of the esophagogastric junction (AEG) are classified according to formerly defined AEG I-III subgroups due to the high surgical impact. To stage local disease, computed tomography of the chest and abdomen and endosonography are reinforced. In contrast, laparoscopy is optional for staging. Mucosal cancers (T1a) should be endoscopically resected "en-bloc" to allow complete histological evaluation of lateral and basal margins. For locally advanced cancers of the stomach or esophagogastric junction (≥T3N+), preferred treatment is preoperative and postoperative chemotherapy. Preoperative radiochemotherapy is an evidence-based alternative for large AEG type I-II tumors (≥T3N+). Additionally, some experts recommend treating T2 tumors with a similar approach, mainly because pretherapeutic staging is often considered to be unreliable. CONCLUSIONS: The German S3 guideline represents an up-to-date European position with regard to diagnosis, staging, and treatment recommendations for patients with locally advanced esophagogastric cancer. Effects of perioperative chemotherapy versus chemoradiotherapy are still to be investigated for adenocarcinoma of the cardia and the lower esophagus.