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Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease globally. miRNAs (miRs) regulate various cellular events that lead to NAFLD. In this study we tested the hypothesis that miR-155 is an important regulator of steatohepatitis and fibrosis pathways. Wild type (WT) or miR-155 deficient (KO) mice received a high fat-high cholesterol-high sugar-diet (HF-HC-HS) for 34 weeks and liver tissues were analyzed. In patients with nonalcoholic steatohepatitis and in the mouse model of HF-HC-HS diet we found increased miR-155 levels in the liver compared to normal livers. Upon HF-HC-HS diet feeding, miR-155 KO mice displayed less liver injury, decreased steatosis, and attenuation in fibrosis compared to WT mice. ALT, triglyceride levels, and genes involved in fatty acid metabolic pathway were increased in WT mice whereas miR-155 KO mice showed attenuation in these parameters. HF-HC-HS diet-induced significant increase in the expression of NLRP3 inflammasome components in the livers of WT mice compared to chow fed diet. Compared to WT mice, miR-155 KO showed attenuated induction in the NLRP3, ASC, and caspase1 inflammasome expression on HF-HC-HS diet. Fibrosis markers such as collagen content and deposition, αSMA, Zeb2, and vimentin were all increased in WT mice and miR-155 KO mice showed attenuated fibrosis marker expression. Overall, our findings highlight a role for miR-155 in HF-HC-HS diet-induced steatosis and liver fibrosis.

Diabetic foot syndrome (DFS) is a complex disease. The best outcomes are reported with the multi-disciplinary team (MDT) approach, where each member works collaboratively according to his/her expertise. However, which health provider should act as the team leader (TL) has not been determined. The TL should be familiar with the management of diabetes, related complications and comorbidities. He/she should be able to diagnose and manage foot infections, including prompt surgical treatment of local lesions, such as abscesses or phlegmons, in an emergent way in the first meeting with the patient. According to the Organization for Economic Co-operation and Development (OECD) reports, Italy is one of countries with a low amputation rate in diabetic patients. Many factors might have contributed to this result, including 1)the special attention directed to diabetes by the public health system, which has defined diabetes as a "protected disease", and accordingly, offers diabetic patients, at no charge, the best specialist care, including specific devices, and 2)the presence of a network of diabetic foot (DF) clinics managed by diabetologists with medical and surgical expertise. The health care providers all share a "patient centred model" of care, for which they use their internal medicine background and skills in podiatric surgery to manage acute or chronic needs in a timely manner. Therefore, according to Italian experiences, which are fully reported in this document, we believe that only a skilled diabetologist/endocrinologist should act as a TL. Courses and university master's degree programmes focused on DF should guarantee specific training for physicians to become a TL.

Bile acids (BAs) activate various dedicated receptors, including the farnesoid X receptor (FXR) and the Takeda G protein‐coupled receptor 5 (TGR5). The FXR agonist obeticholic acid (OCA) is licensed for the treatment of primary biliary cholangitis and has shown promising results in NASH patients, whereas TGR5 agonists target inflammation and metabolism. We hypothesized that FXR and/or TGR5 agonists may be therapeutic in early alcoholic liver disease (ALD) in mice, in which hepatic inflammation plays a major role. OCA, INT‐777, and INT‐767 are BA derivatives with selective agonist properties for FXR, TGR5, or both, respectively. These compounds were tested in two mouse models (3‐day binge model and prolonged Lieber DeCarli diet for 12 days) of early ALD. Serum alanine aminotransferase and liver histology were used to assess liver injury, Oil Red O staining of liver sections to assess steatosis, and real‐time polymerase chain reaction to assess changes in gene expression. In the ethanol binge model, treatment with OCA and INT‐777 decreased hepatic macrovesicular steatosis and protected from ethanol‐induced liver injury. After prolonged ethanol administration, mice treated with OCA, INT‐767, or INT‐777 showed decreased hepatic steatosis, associated with reduced liver fatty acid synthase protein expression, and protection from liver injury. Treatment with BA receptor agonists in both models of ethanol administration modulated lipogenic gene expression, and decreased liver interleukin‐1β mRNA expression associated with increased ubiquitination of NLRP3 inflammasome through cyclic adenosine monophosphate–induced activation of protein kinase A. Conclusion: OCA, INT‐767, or INT‐777 administration is effective in reducing acute and chronic ethanol‐induced steatosis and inflammation in mice, with varying degrees of efficacy depending on the duration of ethanol administration, indicating that both FXR and TGR5 activation can protect from liver injury in ALD models.

Atrial fibrillation (AF) is a complex phenomenon associated with electrical, mechanical, and structural abnormalities of the atria. Ischaemic stroke in AF is only partially understood, but the mechanisms are known to be related to the atrial substrate as well as the atrial rhythm. The temporal dissociation between timing of AF and occurrence of stroke has led to the hypothesis that fibrotic, prothrombotic atrial tissue is an important cause of thrombus formation in patients with AF, independent of the atrial rhythm. Current stroke risk scores are practical, but limited in their capacity to predict stroke risk accurately in individual patients. Stroke prediction might be improved by the addition of emerging risk factors, many of which are expressions of atrial fibrosis. The use of novel parameters, including clinical criteria, biomarkers, and imaging data, might improve stroke risk prediction and inform on optimal treatment for patients with AF and perhaps individuals only at risk of AF.

The airways of patients with cystic fibrosis (CF) are frequently colonized by various filamentous fungi, mainly Aspergillus fumigatus and Scedosporium species. To establish within the respiratory tract and cause an infection, these opportunistic fungi express pathogenic factors allowing adherence to the host tissues, uptake of extracellular iron, or evasion to the host immune response. During the colonization process, inhaled conidia and the subsequent hyphae are exposed to reactive oxygen species (ROS) and reactive nitrogen species (RNS) released by phagocytic cells, which cause in the fungal cells an oxidative stress and a nitrosative stress, respectively. To cope with these constraints, fungal pathogens have developed various mechanisms that protect the fungus against ROS and RNS, including enzymatic antioxidant systems. In this review, we summarize the different works performed on ROS- and RNS-detoxifying enzymes in fungi commonly encountered in the airways of CF patients and highlight their role in pathogenesis of the airway colonization or respiratory infections. The potential of these enzymes as serodiagnostic tools is also emphasized. In addition, taking advantage of the recent availability of the whole genome sequence of S. apiospermum, we identified the various genes encoding ROS- and RNS-detoxifying enzymes, which pave the way for future investigations on the role of these enzymes in pathogenesis of these emerging species since they may constitute new therapeutics targets.

Intracardiac ventricular assist devices (VADs) are increasingly being used in the management of patients with severe heart failure refractory to medical therapy. In the CCU, echocardiography is utilized to confirm appropriate position and function of intracardiac VAD components as part of routine surveillance or in response to concerning signs and symptoms. This chapter will focus on the use of echocardiography in adult patients with durable continuous-flow left ventricular assist devices (LVADs) as well as short-term, percutaneous left- and right-sided Impella VADs.

Background Minimally invasive surgery has been recently recommended for treatment of early-stage non-small cell lung cancer. Despite the recent increase of robotic surgery, the place and potential advantages of the robot in thoracic surgery has not been well defined until now. Methods We reviewed our prospective database for retrospective comparison of our first 28 video-assisted thoracoscopic surgery lobectomies (V group) and our first 28 robotic lobectomies (R group). Results No significant difference was shown in median operative time between the two groups (185 vs. 190 minutes, p = 0.56). Median preincision time was significantly longer in the R group (80 vs. 60 minutes, P 0.0001). The rate of emergency conversion for uncontrolled bleeding was lower in the R group (one vs. four). Median length of stay was comparable (6 days in the R group vs. 7 days in the V group, p = 0.4) with no significant difference in the rate of postoperative complications (eight Grade I in both groups, four Grade III or IV in the V group vs. six in the R group, according to the Clavien-Dindo classification, p = 0.93). No postoperative cardiac morbidity was observed in the R group. Median drainage time was similar (5 days, p = 0.78), with a rate of prolonged air leak slightly higher in the R group (25 vs. 17.8%, p = 0.74). Conclusion Perioperative outcomes are similar even in the learning period but robotic approach seems to offer more operative safety with fewer conversions for uncontrolled bleeding.

Kupffer cell and macrophage (MO) activation contributes to steatosis, inflammation, and fibrosis in alcoholic liver disease (ALD). We found increased frequency of MO, T cells, and expression of C-C chemokine receptor type 2 (Ccr2) and C-C chemokine receptor type 5 (Ccr5) in the livers of patients with ALD, and increased circulating chemokines, C-C chemokine ligand types 2 (CCL2), and C-C chemokine ligand types 5 (CCL5) in patients with alcoholic hepatitis. We hypothesized that inhibition of CCL2 signaling with the dual CCR2/5 inhibitor, cenicriviroc (CVC), would attenuate ALD. In a mouse model of ALD, liver injury (alanine aminotransferase [ALT]) and steatosis were prevented by CVC whether administered as "prevention" throughout the alcohol feeding or as "treatment" started after the development of ALD. Alcohol-induced increases in early liver fibrosis markers (sirius red, hydroxyproline, and collagen-1) were normalized by both modes of CVC administration. We found that prevention and treatment with CVC reversed alcohol-related increases in liver mRNA and protein expression of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, and CCL2. CVC administration regimens prevented the increase in infiltrating MO (F4/80lo CD11bhi ) and reduced proinflammatory Ly6Chi MO in livers of alcohol-fed mice. CVC increased liver T-cell numbers and attenuated Il-2 expression without an effect on CD69+ or CD25+ T-cell expression. In vitro, CVC inhibited CCL2-induced increases in hepatocyte fatty acid synthase (Fasn) and adipose differentiation-related protein (Adrp), whereas it augmented acyl-coenzyme A oxidase 1 (Acox-1), proliferator-activated receptor gamma co-activator alpha (Pgc1α) and uncoupling protein 2 expression, suggesting mechanisms for attenuated hepatocyte steatosis. We found that CCL2 and CCL5 sensitized hepatocytes to lipopolysaccharide-induced liver injury (TNF-α, ALT, and lactate dehydrogenase release). Alcohol feeding induced apoptosis (poly ADP-ribose polymerase [PARP] and caspase-3 [CASP-3] cleavage) and pyroptosis (gasdermin D [GSDMD] cleavage) in livers, and CVC prevented both of these forms of cell death. Conclusion: Together, our data demonstrate preclinical evidence for CCR2/CCR5 inhibition with CVC as a potent intervention to ameliorate alcohol-induced steatohepatitis and liver damage.

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BackgroundAtrial fibrillation (AF) is common in patients with the HeartMate II (HMII) left ventricular assist device (LVAD), but the impact of AF on clinical outcomes is uncertain.ObjectivesThis study sought to determine the effect of AF on outcomes in patients with the HMII LVAD.MethodsRecords of 106 patients who underwent HMII implantation at a single center were reviewed. The associations of paroxysmal atrial fibrillation (PAF) and persistent atrial fibrillation (PeAF) with survival, heart failure (HF) hospitalization, bleeding, and thromboembolism were examined using Kaplan-Meier survival analysis and Cox proportional hazards regression.ResultsMean age was 56.6 ± 11.4 years, 87.7% of the implants were intended as a bridge to transplantation, and median length of support was 217 days (range: 1 to 952 days). AF was present in 55 patients (51.9%); 36 patients (34.0%) had PAF and 19 (17.9%) had PeAF. Twenty-one patients (19.8%) died, and 18 (17.0%) were hospitalized for HF. There were 0.75 major bleeding events and 0.28 thromboembolic events per patient year of follow-up. PAF was not associated with increased mortality, HF hospitalization, bleeding, or thromboembolism. PeAF, however, was an independent predictor of the composite endpoint of death or HF hospitalization (hazard ratio: 3.54; 95% confidence interval: 1.52 to 8.25; p < 0.01). Although there was no increase in bleeding or thromboembolism, patients with AF had thromboembolic events at higher international normalized ratios (INRs).ConclusionsAlthough PAF is not associated with worse outcomes in patients with the HMII LVAD, PeAF may be associated with increased mortality and HF hospitalization. Patients with AF also may have thromboembolic events at higher INR levels.

International audience; The increasing use of array-CGH in malformation syndromes with intellectual disability could lead to the description of new contiguous gene syndrome by the analysis of the gene content of the microdeletion and reverse phenotyping. Thanks to a national and international call for collaboration by Achropuce and Decipher, we recruited four patients carrying de novo overlapping deletions of chromosome 9q33.3q34.11, including the STXBP1, the LMX1B and the ENG genes. We restrained the selection to these three genes because the effects of their haploinsufficency are well described in the literature and easily recognizable clinically. All deletions were detected by array-CGH and confirmed by FISH. The patients display common clinical features, including intellectual disability with epilepsy, owing to the presence of STXBP1 within the deletion, nail dysplasia and bone malformations, in particular patellar abnormalities attributed to LMX1B deletion, epistaxis and cutaneousmucous telangiectasias explained by ENG haploinsufficiency and common facial dysmorphism. This systematic analysis of the genes comprised in the deletion allowed us to identify genes whose haploinsufficiency is expected to lead to disease manifestations and complications that require personalized follow-up, in particular for renal, eye, ear, vascular and neurological manifestations.

Women need multipurpose prevention products (MPTs) that protect against sexually transmitted infections (STIs) and provide contraception. The Population Council has developed a prototype intravaginal ring (IVR) releasing the non-nucleoside reverse transcriptase inhibitor (NNRTI) MIV-150 (M), zinc acetate (ZA), carrageenan (CG) and levonorgestrel (LNG) (MZCL IVR) to protect against HIV, HSV-2, HPV and unintended pregnancy. Our objective was to evaluate the anti-SHIV-RT activity of MZCL IVR in genital mucosa. First, macaque vaginal tissues were challenged with SHIV-RT in the presence of (i) MIV-150 ± LNG or (ii) vaginal fluids (VF); available from studies completed earlier) collected at various time points post insertion of MZCL and MZC IVRs. Then, (iii) MZCL IVRs (vs. LNG IVRs) were inserted in non-Depo Provera-treated macaques for 24h and VF, genital biopsies, and blood were collected and tissues were challenged with SHIV-RT. Infection was monitored with one step SIV gag qRT-PCR or p27 ELISA. MIV-150 (LCMS/MS, RIA), LNG (RIA) and CG (ELISA) were measured in different compartments. Log-normal generalized mixed linear models were used for analysis. LNG did not affect the anti-SHIV-RT activity of MIV-150 in vitro. MIV-150 in VF from MZC/MZCL IVR-treated macaques inhibited SHIV-RT in vaginal mucosa in a dose-dependent manner (p

Unfractionated heparin or low-molecular-weight heparin for preventing thrombosis after infrainguinal arterial bypass procedures are commonly used without validation. We decided to assess both attitudes with the help of a retrospective study. We reported a non-inferiority between low-molecular-weight heparin and unfractionated heparin. It is possible to use unfractionated heparin in case of renal failure and a low molecular weight heparin when the clearance is normal because both therapies are equivalent.

What's known on the subject? and What does the study add? With the present study, we aimed to provide a global picture of the molecular processes that are activated by CN injury. The present study used genomic expression profiling to identify candidate genes that might be useful targets in the CN recovery process and, thus, the ultimate preservation of penile erection. Regeneration of the CN and axonal outgrowth clearly involve changes in multiple biochemical pathways that have never been investigated by microarray analysis. We analyzed global gene expression in the major pelvic ganglion at early stages (48 h and 14 days) after CN injury and focused on the detection of changes in genes related to nervous tissue repair and proliferation. The findings of the present study provide important insight into the molecular systems affected by CN injury and identify candidate genes that may be utilized for novel molecular-based therapies for the preservation and protection of the CN during RP. OBJECTIVES • To to examine the complexity of the many molecular systems involved in supporting cavernous nerve (CN) repair and regeneration in a rat model of bilateral crush injury utilizing a microarray analysis approach. Erectile dysfunction (ED) is a common clinical complication after prostate cancer treatment by radical prostatectomy, and recovery of erectile function can take as long as 2 years. • There are gaps in our understanding of the autonomic pelvic innervation of the penis that still need to be addressed for the development of an adequate treatment strategy for post-prostatectomy ED. The molecular mechanisms of the intrinsic ability of CN to regenerate after an injury have not been elucidated. MATERIALS AND METHODS • We analyzed global gene expression in the major pelvic ganglion 48 h and 14 days after CN injury. Overall, a comparative analysis showed that 325 genes changed at the 48-h time point and 114 genes changed at 14 days. There were 60 changed genes in common with both time points. • Using the Ingenuity Pathway Analysis® system (Ingenuity Systems, Inc., Redwood City, CA, USA), we were able to analyze the significantly changed genes that were unique and common to each time point by biological function. • We focused on the detection of changes related to nervous tissue repair and proliferation, molecular networks of neurotrophic factors, stem cell regulation and synaptic transmission. RESULTS • There was strong evidence of the early mobilization of genes involved in repair and neuroprotection mechanisms (SERPINF1, IGF1, PLAU/PLAUR, ARG1). • Genes related to nervous system development (ATF3 GJA1, PLAU, SERPINE1), nerve regeneration (SERPINE2, IGF1, ATF3, ARG1) and synaptic transmission (GJC1, GAL) were changed. • Several genes related to proliferation as well as apoptosis (A2M, ATF3, C3, EGR4, FN1, GJA1, GAL) were also changed, possibly as part of a protective mechanism or the initiation of remodelling. CONCLUSIONS • The results obtained show that multiple biological processes are associated with injury and repair of the CN and provide a systematic genome-wide screen for neurotrophic and/or inhibitory pathways of nerve regeneration. • These data identify the candidate genes that may be utilized in novel molecular-based therapies for the preservation and protection of the CN during radical prostatectomy.

Background: HPV is the most common sexually transmitted disease in many regions of the world. 15% was found in women aged 15-19 years but the highest incidence of infection from HPV can be found in sexually active adolescents: between 50% and 80% of them catch the infection within two to three years from their first sexual relationship. Methods: A community randomized trial regarding HPV infection and HPV vaccination, and sexual health was carried out, in a sample of secondary school students. Peer education intervention was carried out and 2 follows-up were carried out after the educative intervention to evaluate the effective outcomes in a 1-year follow up of the effect of peer health education on primary prevention knowledge, attitude and behaviour towards HPV. Results: The sample of 900 students, with age of 16.6 ± 1.4 ds, 34.4% of which have sexual relationships. 64.6% of students in the experimental group said that they were aware of HPV, 83.4% were aware of how it is transmitted and 71.1% knew HPV vaccination, 54.7% perceived the level of danger with significant gender-related differences the percentages increased at T1. At T0, 14.1% of females were vaccinated: T1 they were 17.5% and 19.2% at T2. The main factors associated with the students’ propensity to vaccination were: having at least one sister; being in favor of vaccinations in general; knowing that the vaccine is aimed at preventing cervical cancer; and being aware that they could be infected by HPV. Conclusions: The study carried out highlights important differences between the experimental group and the control group in terms of knowledge but, most importantly, in terms of behaviour and it proves how the application of new educational methods based on the involvement of youngsters right from the initial stages of the project can help them to change their behaviour and maintain it in time.

The purposes of this study were: (1) to compare our data with those reported in the general population; (2) to find a factor implicated in repetitive accidents; (3) to look for a possible genetic factor; and (4) to evaluate whether or not the risk of recurrence was the same in a family with two or more infants having died of sudden intant death syndrome (SIDS) as in the general population. We study retrospectively 77 files which constitute a group of 30 families which was analysed with reference to a list of data laid out in the shape of genealogical trees. Our study shows that risk factors are similar to those described previously and repetitive among siblings or cousins. The rate of recurrence is not available for the general population. On studying some family trees, we can speculate on the existence of an autosomal dominant gene with incomplete penetrance.

Diabetes results in a myriad of vascular complications, often referred to as diabetic vasculopathy, which encompasses both microvascular [erectile dysfunction (ED), retinopathy, neuropathy, and nephropathy] and macrovascular complications (hypertension, coronary heart disease, and myocardial infarction). In diabetic animals and patients with ED, there is decreased opiorphin or opiorphin-related gene expression in corporal tissue. Both opiorphin and the rat homologous peptide sialorphin are found circulating in the plasma. In the present study, we investigated if diabetes induced changes in plasma sialorphin levels and if changes in these levels could modulate the biochemistry and physiology of vascular smooth muscle. We show that circulating sialorphin levels are reduced in a rat model of type I diabetes. Intracorporal injection of plasmids expressing sialorphin into diabetic rats restores sialorphin levels to those seen in the blood of nondiabetic animals and results in both improved erectile function and blood pressure. Sialorphin modulated the ability of C-type natriuretic peptide to relax both corporal and aortic smooth muscle strips and of bradykinin to regulate intracellular calcium levels in both corporal and aortic smooth muscle cells. We have previously shown that expression of genes encoding opiorphins is increased when erectile function is improved. Our findings thus suggest that by affecting circulating levels of opiorphin-related peptides, proper erectile function is not only an indicator but also a modulator of overall vascular health of a man.

The MaxiK potassium channel is regulated by voltage and intracellular calcium, and plays a critical role in regulating intracellular calcium concentration ([Ca(2+) ](i)), which is the ultimate determinant of smooth muscle tone. Tight control of corpus cavernosum smooth muscle (CCSM) tone is critically important and misregulation can result in erectile dysfunction.Because of the tight functional linkage of MaxiK and calcium channel activity, the aim of this study was to determine the effects of silencing and pharmacological inhibition of MaxiK on calcium homeostasis and intercellular calcium signaling in CCSM cells.We compared changes in the basal intracellular [Ca(2+) ](i) and parameters defining intercellular calcium wave (ICW) spread in 48 hours MaxiK silenced CCSM cells vs. acute blockade of the channel with iberiotoxin. To analyze changes occurring in gene expression we performed micro-array analysis following MaxiK silencing for 48 hours.Changes in Fura-2 fluorescence intensities were measured to evaluate basal [Ca(2+) ](i) levels and ICW parameters. Microarray analysis of global gene expression was performed.Forty-eight hours after MaxiK silencing the basal [Ca(2+) ](i) , the ICW amplitude and spread among CCSM cells were not markedly different in silenced compared to mock transfected controls, whereas short-term blockade significantly increased basal [Ca(2+) ](i) level and amplified Ca(2+) signaling among CCSM cells. Micro-array analysis showed that several genes within Ca(2+) homeostasis and smooth muscle tone regulation pathways had significantly altered expression.Our results indicate that while short-term blockade of the MaxiK channel is associated with an increase in basal [Ca(2+) ](i), Ca(2+) homeostasis is restored during the 48 hours period following silencing. We hypothesize that the different pathways regulating [Ca(2+) ](i) and CCSM tone are linked through molecular crosstalk and that their coordinated regulation is part of a compensatory mechanism aimed to maintain Ca(2+) homeostasis and CCSM tone.

Objective The aim of this study was to assess the right placement of the double lumen endotracheal tube with fluoroscopic guidance, which is used in first intention prior to the fiberscope in our institution. Methods This was a prospective observational study. The study was conducted in vascular and thoracic operating rooms. We enrolled 205 patients scheduled for thoracic surgery, with ASA physical statuses of I ( n = 37), II ( n = 84), III ( n = 80), and IV ( n = 4). Thoracic procedures were biopsy ( n = 20), wedge ( n = 34), culminectomy ( n = 6), lobectomy ( n = 82), pneumonectomy ( n = 4), sympathectomy ( n = 9), symphysis ( n = 47), and thymectomy ( n = 3). The intubation with a double lumen tube was performed with the help of a laryngoscope. Tracheal and bronchial balloons were inflated and auscultation was performed after right and left exclusions. One shot was performed to locate the position of the bronchial tube and the hook. Fluoroscopic guidance was used to relocate the tube in case of a wrong position. When the fluoroscopic guidance failed to position the tube, a fiberscope was used. Perioperative collapse of the lung was assessed by the surgeon during the surgery. Results Correct fluoroscopic image was obtained after the first attempt in 58.5% of patients therefore a misplaced position was encountered in 41.5%. The fluoroscopic guidance allowed an exact repositioning in 99.5% of cases, and the mean duration of the procedure was 8 minutes. A fiberscope was required to move the hook for one patient. We did not notice a moving of the double lumen endotracheal tube during the surgery. The surgeon satisfaction was 100%. Conclusion The fluoroscopy evidenced the right position of the double lumen tube and allowed a right repositioning in 99.5% of patients with a very simple implementation.

Background Despite the advent of effective oral therapies for erectile dysfunction (ED), many patients are not successfully treated, and side effects have been documented. Objective To further evaluate the potential utility of naked DNA-based gene transfer as an attractive treatment option for ED. Design, setting and participants The effects of gene transfer on erectile function and sexual behavior were evaluated in eight male cynomolgus monkeys with ED secondary to moderately severe, diet-induced atherosclerosis. Intervention Following establishment of baseline characteristics, animals were subjected to intracavernous injection of a smooth-muscle–specific gene transfer vector (pSMAA- hSlo ) encoding the pore-forming subunit of the human large-conductance, calcium-sensitive potassium channel (Maxi-K). Measurements For the sexual behavior studies, 2 wk of baseline data were obtained, and then animals were placed in the presence of estrogen-implanted females ( n =2) three times per week for 30min, and sexual behavior was recorded. The intracavernous pressure response to papaverine injection was also monitored. Results and limitations Dramatic changes in erectile function and sexual behavior were observed after intracorporal gene transfer. The frequency of partial (6±2 to 10±2) and full (2±1.5 to 5±1.4) erections were significantly increased, with a parallel 2–3-fold increase in the duration of the observed erections. The frequency and latency of ejaculation were increased and decreased, respectively. Frequency and duration of grooming by the female were increased, and the latency decreased. Increased latency and decreased frequency of body contact was also observed, and this is characteristic of the typical drop in consort intimacy that occurs after mating in most macaque species. In addition, an increased responsiveness to intracavernous papaverine injection was observed. Conclusions The data indicate that intracorporal Maxi-K–channel gene transfer enhances erectile capacity and sexual behavior; the data imply that increased erectile function per se may lead to increased sexual function.

Acute coronary syndrome (ACS) is a common and sometimes lethal event, usually precipitated by sudden rupture and thrombosis of an atherosclerotic plaque. Patients presenting with ACS can be rapidly risk stratified based on signs, symptoms, electrocardiogram, and biomarkers. There is a new generation of potent and reliable antiplatelet drugs, which in concert with anticoagulation and rapid revascularization, can preserve myocardium and save lives. When choosing how to revascularize, hemodynamically stable patients with diabetes mellitus and complex coronary disease benefit more from coronary artery bypass grafting rather than percutaneous coronary intervention. Despite optimal treatment, ACS can result in deadly complications such as cardiogenic shock. Supportive care is paramount, but despite its widespread use, the utility of intraaortic balloon counterpulsation is uncertain. In the future, advanced coronary imaging may enhance preventative care, novel molecular targets will help expand treatment options, and cell-based regenerative therapies may aid myocardial recovery after acute coronary syndrome.

Background: In a prospective randomized double-blind study, the analgesic effect produced by sub-Tenon infiltration was compared with classic analgesic drugs in patients scheduled for posterior segment surgery under general anaesthesia. Methods: One hundred patients were randomized into two groups of 50. One group received sub-Tenon infiltration (group 1) with 3 mL of bupivacaine 0.50% by the surgeon before the end of the surgery and the other (group 2) received only classical analgesic drugs postoperatively. A visual analogue scale (VAS) (graded from 1 to 10) was used to assess pain. For both groups, when VAS was between 1 and 3 paracetamol (3 g/24 h) associated with ketoprofen (200 mg/24 h) was given; between 3 and 6 nalbuphine (0.2 mg/kg slowly intravenously repeated every 4 h if necessary) was given; and over 6 morphine was given. Morphine 1 mg was injected every 2 min until VAS below 3 was obtained. Results: All patients in group 2 (control) experienced pain in the recovery room period; however, no patient in group 1 required analgesic drugs in the first 6 h after the sub-Tenon infiltration. In the recovery room period, the VAS pain score in patients who received sub-Tenon infiltration (group 1) was 0.6 ± 1.3 (mean ± SD) compared to 3.4 ± 2.2 in group 2. The difference was statistically significant (P = 0.000001). All patients in group 2 asked for analgesic drugs in the recovery room, some of whom required morphine. Despite the administration of drugs the pain score was statistically higher in group 2. Between the end of the recovery room period and the 6th hour, the VAS pain score in group 1 was statistically lower. From the 6th until the 24th hour, the pain score was not statistically significantly different between the groups. Regarding consumption of analgesic drugs from the recovery room until the 24th hour, the consumption of level 1 analgesic drugs (paracetamol, ketoprofen) and level 3 (morphine) was statistically lower in group 1 (P = 0.0009). The difference was not significant for level 2, probably because the number of patients was not sufficient. Conclusion: Sub-Tenon infiltration with 3 mL of bupivacaine 0.50% offers excellent postoperative analgesia for about 6 h and is an excellent alternative to classical drugs. Furthermore, it is highly reliable and safe.

The use of neuroleptics in the elderly has been a topic of debate since 2005 when the US Food and Drug Administration issued a black-box warning of increased risk of mortality in elderly patients with dementia-related psychosis. Antipsychotic alternatives such as divalproex are sometimes favored on an "off-label" basis to manage agitation in the demented elderly, and antipsychotic use is often clinically necessary to treat psychosis in older adults, with or without dementia. Concurrently, risk for iatrogenic corrected QT (QTc) prolongation on electrocardiogram (ECG) remains a concern with the use of many antipsychotic agents because of its associated potential for fatal arrhythmias.

Objectives No guidelines are available in France for peribulbar block for eye procedures. It is our hypothesis that continued use of acetyl salicylic acid for forestalling myocardial or cerebrovascular ischemic events does not increase the risk of hemorrhage, compared with discontinuation of its use in patients who undergo eye procedures under peribulbar block. Methods For this prospective control study we enrolled two groups of 500 patients scheduled for intra-ocular eye surgery requiring a peribulbar block. Patients treated with acetyl salicylic acid were included in group A (500 patients). Patients who had never been treated with acetyl salicylic acid constituted the control group (group B: 500 patients). Hemorrhages were graded as follows: 1 = spot ecchymosis; 2 = lid ecchymosis involving half of the lid surface area or less; 3 = lid ecchymosis all around the eye, without increase in intra-ocular pressure; 4 = retrobulbar hemorrhage with increased intraocular pressure. Results In group A, lid hemorrhages (grade 1) were observed in 30 patients (6.0%). No grade 2, 3 or 4 hemorrhages were encountered in this group. In group B, lid hemorrhage (grade 1) was observed in 20 patients (4.0%) and grade 2 in one patient (0.2 %), but no grade 3 or 4 hemorrhages were encountered. Statistical tests showed the absence of significance between both groups. Conclusion We conclude that between the groups with and without pre-operative acetyl salicylic acid the occurrence rate of lid hemorrhage was not significant in peribulbar block.

Background and objectives: We carried out a prospective study in order to evaluate the efficacy and safety of peribulbar anaesthesia supplemented by a sub-Tenon injection in case of inadequate analgesia during vitreoretinal surgery. Methods: We performed 300 consecutive vitreoretinal procedures. Patients received a mean volume of 17±4.5 ml of a mixture of etidocaine 1%, bupivacaine 0.50% and hyaluronidase (25 UI/ml). Supplementation was represented by a sub-Tenon infiltration of lidocaine 2% (2 or 3 ml). This volume was not included in the mean volume. Results: Analgesia was adequate throughout surgery without any supplementation in 85% of cases and with a sub-Tenon infiltration in 99%. Akinesia was complete in 82%, mild in 15% and absent in 3% of cases. The sub-Tenon injection was performed immediately before starting the procedure in 58% of cases and during the surgery with a delay of 80±21 min in 42%. Eleven patients (3.66%) were agitated during surgery and two of them needed a general anaesthesia to allow for the procedure. Generalised epilepsy was encountered in two patients (0.66%) immediately after the peribulbar injection in one patient and 15 min later in the other. The systolic blood pressure severely decreased between 60 to 70 mm Hg 40 min after the accomplishment of the peribulbar in 2 patients and at 90 min in 2 others. Conclusion: Our results demonstrate that peribulbar anaesthesia alone offers excellent analgesia in 85% of patients and supplemented by a sub-Tenon injection in 99%.

International audience; Recent reports have shown that amyloid beta deposits in the brains of Alzheimer's disease patients consist mainly of two distinct species of amyloid beta protein (Abeta) with different C-termini, Abeta1-42 (Abeta42) and Abeta1-40 (Abeta40). The nature of the Abeta species in Microcebus murinus brain was investigated immunocytochemically using polyclonal antibodies with clear specificity for the Abeta42 and Abeta40 C-termini. The cortical vascular deposits were immunopositive for both Abeta42 and Abeta40. However, most of the diffuse plaques were strongly positive for Abeta42 whereas only a subset of deposits were positive for Abeta40. Numerous cortical plaques were Abeta42-immunopositive but tested negative for Abeta40. This suggests that Abeta42 is probably associated with early stages of plaque maturation. This neuropathological feature reminiscent of that observed in brains affected by Alzheimer's disease further supports the idea that M. murinus could be used as a potential model of the early stages of this neurological disease.

Many children with esophagitis demonstratehistological changes without gross evidence ofesophagitis by esophagoscopy. The effect of omeprazoleon the histological healing of esophagitis in childrenis unknown. Therefore, the aim of this study wasto determine the effect of omeprazole on refractoryhistological esophagitis in pediatric patients. Eighteenpatients with histological evidence of esophagitis and recurrent symptoms despite therapy withH2-receptor antagonists and prokinetic agentswere prospectively treated with omeprazole. Dosing wasadjusted by monitoring intragastric pH, andesophagoscopy was repeated after 8-12 weeks of omeprazoletreatment. Two patients did not complete the study dueto either worsening symptoms or hypergastrinemia. Of theremaining patients, 76% were asymptomatic with omeprazole treatment and 24% reportedimprovement in their symptoms. Approximately 40%demonstrated complete histological healing of theiresophagitis. Three patients (17%) had persistentelevations in serum gastrin levels while on omeprazoletreatment, which was associated with both youngerpatient age and higher omeprazole dosing; however, allelevated gastrin levels returned to normal afterdiscontinuation of the medication. All patients had recurrenceof their symptoms after completing a course ofomeprazole, even patients with complete histologicalhealing. Omeprazole is efficacious in treating children with esophagitis refractory toH2-receptor antagonist and prokinetic agents.However, none of the patients were able to discontinueacid suppressive therapy even after documented healingof their esophagitis.

We report a case of endophthalmitis who underwent a vitreous biopsy to assess sensitivity and to inject broad-spectrum intraocular antibiotics. Minimal inhibitory concentration (MIC) values of antibiotics against a coagulase-negative staphylococcus and Proprionibacterium acnes were also assessed.

Background— The prognosis for patients experiencing ventricular arrhythmias (VAs) while on continuous flow left ventricular assist device (LVAD) support has not been well elucidated. Accordingly, the role of implantable cardioverter-defibrillators (ICDs) in this patient population remains undefined. Methods and Results— Records of 106 consecutive patients undergoing implantation of the HeartMate II LVAD at a single center were reviewed. For patients surviving >30 days postimplant (98 patients), the impact of VAs and ICDs on survival was analyzed. Mean age was 56.6±11.4 years, 82.1% were male, 42.5% had an ischemic cardiomyopathy, 87.7% were bridge to transplantation, and median length of support was 217 days. Twenty-one (19.8%) patients died, 60 (56.6%) survived to transplantation, and 25 patients (23.6%) reached the end of study, had the LVAD explanted, or were lost to follow-up. Post-LVAD VAs occurred in 37 patients (34.9%) but were not associated with increased mortality (hazard ratio, 0.58 [0.18–1.90]). Sixty-two (63.3%) patients had an active ICD, and 36 (36.7%) patients had no ICD or an inactivated ICD post-LVAD. Patients with an ICD were more likely to be INTERMACS (Interagency Registry for Mechanically Assisted Circulatory Support) level 3 or 4 at the time of implant (54.8% versus 33.3%; P =0.04). An appropriate shock was delivered in 27.3% of patients, but the presence of an active ICD was not associated with improved survival (hazard ratio, 1.12 [0.37–3.35]). Conclusions— VAs are common in patients with continuous flow LVADs. Although some episodes may be clinically significant, VAs are not associated with a worse prognosis, and concomitant ICDs in these patients may not reduce mortality.

A case of systemic ropivacaine toxicity from a continuous thoracic paravertebral block in an adult patient who received a lobectomy is presented. The catheter was placed by the surgeon. Eleven hours after the start of the infusion, the patient experienced an arrhythmia leading to death. The total venous plasma concentration of ropivacaine was high (3.2 μg/mL). Furthermore, the patient had severe hypoalbuminemia (albumin 24 g/L), which resulted in the increase of the unbound ropivacaine plasma concentration that was responsible for the toxic side effects.

To compare the utilization of echocardiography as a diagnostic tool by internists and cardiologists.Retrospective study.Tertiary care university hospital.Indications and clinical utility of echocardiographic studies ordered by cardiologists (group A, n = 301) and internists (group B, n = 297) were compared by chart review. The two groups of patients were analyzed to determine if the studies detected new cardiac pathology and/or altered patient management.The proportion of studies with abnormal results were similar in both groups (19% versus 14%, P0.05). The results of echocardiography, however, led to a change in management more often when the study was ordered by cardiologists (16% versus 10%, P0.05). A significantly greater proportion of studies were ordered for evaluation of valvular function by internists (44% versus 33%, P0.05). Echocardiography detected valvular abnormalities in a similar proportion of cases in groups A and B (14% versus 10%, P0.05). However, diagnostic yield was very poor when the study was performed in patients with suspected mitral valve prolapse in both groups. Cardiologists utilized echocardiography more often for evaluation of left ventricular function (35% versus 18%, P0.01) and in the setting of atherosclerotic heart disease for detecting wall motion abnormalities (14% versus 5%, P0.01).Diagnostic yield of echocardiography is similar when ordered by internists and cardiologists. With the information obtained, management is altered in a slightly greater proportion of cases involving a cardiologist. This may be due to utilization of echocardiography more often for estimating left ventricular function and for detecting wall motion abnormalities by cardiologists.

Hypereosinophilic syndrome (HES) is associated with cardiac manifestations including thrombi, endomyocardial fibrosis (EMF), and valvular abnormalities. Fibrosis of the right ventricle (RV) with apical retraction of the tricuspid valve (TV) has been reported. Distinguishing Ebstein's from EMF has

Source Citation van den Ham HA, Klungel OH, Singer DE, Leufkens HG, van Staa TP. Comparative performance of ATRIA, CHADS2, and CHA2DS2-VASc risk scores predicting stroke in patients with atrial fib...

International audience; OBJECTIVE: We sought to evaluate the safety and efficacy of TG4001 in patients with human papillomavirus (HPV) 16-related cervical intraepithelial neoplasia (CIN) 2/3 at 6 and 12 months. STUDY DESIGN: In all, 21 patients with HPV 16-related CIN 2/3 received 3 weekly subcutaneous injections of TG4001. Regression of the CIN 2/3 lesion and the clearance of HPV 16 infection were monitored by cytology, colposcopy, and HPV DNA/messenger RNA (mRNA) detection. A clinical response was defined by no CIN 2/3 found on conization, or no conization performed because not suspected at cytology or colposcopy. RESULTS: Ten patients (48%) were evaluated as clinical responders at month 6. Nine patients experienced an improvement of their HPV 16 infection, by mRNA ± DNA eradication. HPV 16 mRNA clearance was associated with CIN 2/3 cytologic and colposcopic regression in 7 of 10 patients. At month 12, 7 of 8 patients without conization reported neither suspicion of CIN 2/3 relapse nor HPV 16 infection. The remaining patient was lost to follow-up. CONCLUSION: These promising data warrant further development of TG4001 in CIN 2/3 treatment.

Normal human peripheral blood mononuclear cells (PBMC) produced IgE when stimulated with IL-4. In the present report it was shown that beta 2-adrenoceptor agonists, salbutamol and fenoterol, potentiated the IL-4-induced IgE production without significantly affecting the expression of the low affinity receptor for IgE at the cell surface of monocytes and B lymphocytes. However, beta 2-adrenoceptor agonists were shown to enhance at day 7 the IL-4-induced release of the soluble form of CD23 (sCD23) by PBMC. This effect was specific since a beta-adrenoceptor antagonist, D,L-propranolol, inhibited the IL-4-induced IgE production by these cells. Alternatively, the beta 2-adrenoceptor agonists inhibited the production by these cells of interferon-gamma (IFN-gamma) but did not affect the production of IL-4 when stimulated with phytohemagglutinin A + a phorbol ester. These data suggest that beta 2-adrenoceptor agonists influence the IL-4-induced IgE production in humans by enhancing the release of sCD23 and inhibiting the production of endogenous IFN-gamma. In addition to the effect on the IL-4-induced IgE production it was shown that beta 2-adrenoceptor agonists potentiated the effect of IL-4 on a human promonocytic cell line, U 937, by enhancing CD23 expression and release and by inducing the differentiation of these cells into monocyte-like cells. Taken together, these data indicate that beta 2-adrenoceptor agonists potentiated the effect of IL-4 and that this functional interaction is different considering the cell-lineage and the stage of differentiation of these cells.

A case of temporary quadriplegia following a continuous thoracic paravertebral block in an adult patient scheduled for video-assisted thoracoscopy is presented. An 18-gauge Tuohy needle was inserted under direct vision by the surgeon but the tip of the catheter was not localized. Postoperatively, the patient developed temporary quadriplegia 90 minutes after the start of a continuous infusion of ropivacaine 0.2%. Imaging studies showed that the catheter was localized in the intrathecal space.

Vcsa1 plays an important role in the erectile physiology of the rat. We conducted experiments to determine if erectile function, testosterone levels and Vcsa1 expression were correlated. In orchiectomized rats, total testosterone in blood fell from an average of 4ng/ml to 6-fold) decreased. Injection of orchiectomized animals with testosterone (2mg in 100ml sesame oil every 4 days for two weeks) restored average levels of testosterone to 2ng/ml, increased erectile function and significantly increased Vcsa1 expression. In isolated corporal cells there was testosterone dependent Vcsa1 expression. However, intracorporal injection of orchiectomized animals with a plasmid expressing Vcsa1 or its gene product Sialorphin (previously demonstrated to improve erectile function in old animals) gave no significant improvement in erectile function. Also, the ability of Sialorphin to reduce tension in corporal smooth muscle strips isolated from orchiectomized animals was impaired compared to controls.

We identified molecular markers of erectile function, particularly those responding to erectile dysfunction treatment.Sprague-Dawley retired breeder rats were intracorporeally injected with pVAX-hSlo, pSMAA-hSlo or the control plasmid pVAX. One week later the intracorporeal pressure-to-blood pressure ratio and gene expression were determined by microarray analysis and quantitative reverse transcriptase-polymerase chain reaction. Rat corporeal cells were transfected in vitro with pVAX-hSlo, pSMAA-hSlo or pVAX and the change in gene expression was determined. We also determined whether Vcsa1 expression was changed after pharmacotherapy using tadalafil.Animals treated with vectors expressing hSlo had significantly improved erectile function compared to that in controls, accompanied by changed expression of a subset of genes. Vcsa1 was one of the genes that was most changed in expression (the third of approximately 31,000 with greater than 10-fold up-regulation). Changes in gene expression were different than those observed in corporeal cells transfected in vitro, distinguishing gene expression changes that were a direct effect of hSlo over expression. When tadalafil was administered in retired breeder rats, the Vcsa1 transcript increased 4-fold in corporeal tissue compared to that in untreated controls.Our study identifies a set of genes that are changed in response to improved erectile function, rather than as a direct effect of treatment. We noted Vcsa1 may act as marker of the restoration of erectile function after gene transfer and pharmacotherapy.

Carpal tunnel syndrome (CTS) is a major, costly public health issue that could be dramatically affected by the identification of additional conservative care treatment options. Our study aimed to evaluate the effectiveness of two distinct massage therapy protocols on strength, function, and symptoms associated with CTS.This was a randomized pilot study design with double pre-tests and subjects blinded to treatment group assignment.The setting for this study was a wellness clinic at a teaching institution in the United States.Twenty-seven (27) subjects with a clinical diagnosis of CTS were included in the study.Subjects were randomly assigned to receive 6 weeks of twice-weekly massage consisting of either a general (GM) or CTS-targeted (TM) massage treatment program.Dependent variables included hand grip and key pinch dynamometers, Levine Symptom and Function evaluations, and the Grooved Pegboard test. Evaluations were conducted twice during baseline, 2 days after the 7th and 11th massages, and at a follow-up visit 4 weeks after the 12th massage treatment.A main effect of time was noted on all outcome measures across the study time frame (p0.001); improvements persist at least 4 weeks post-treatment. Comparatively, TM resulted in greater gains in grip strength than GM (p = 0.04), with a 17.3% increase over baseline (p0.001), but only a 4.8% gain for the GM group (p = 0.21). Significant improvement in grip strength was observed following the 7th massage. No other comparisons between treatment groups attained statistical significance.Both GM and TM treatments resulted in an improvement of subjective measures associated with CTS, but improvement in grip strength was only detected with the TM protocol. Massage therapy may be a practical conservative intervention for compression neuropathies, such as CTS, although additional research is needed.

Background: Growth failure frequently complicates Crohn's disease in childhood. Abnormalities in the growth hormone (GH)/insulin-like growth factor-1 axis may occur. The effects of administered GH on growth have not been studied previously in a randomized trial. Methods: Seven children (6 boys and 1 girl; age, 11.9-16 yr) with Crohn's disease and growth failure were enrolled. In phase 1, patients were randomized to either GH (0.05 mg/kg per day) or placebo; in phase 2, patients who received placebo during the first year received GH for various time periods. Follow-up was every 3 months for up to 2 years. Results: During placebo treatment (4 patients), mean height-for-age z score (haz) increased 0.23 in the first half year and 0.55 in the second half year. The mean improvement in haz during the first half year of GH treatment (7 patients) was 0.13; during the second half year (5 patients), haz decreased 0.01. Effects of GH varied among patients; 2 patients grew only when nutritional supplementation was added. Observed changes were not statistically significant; however, the number of patients studied was small, and statistical analyses could have been affected by sample size. Serum insulin-like growth factor-1 levels correlated with height velocity. Only 2 patients later reached expected adult height. Conclusions: In this pilot study, GH treatment at the dose given did not stimulate growth in children with Crohn's disease and short stature. Whether or not GH plus nutritional therapy would be effective in promoting sustained catch-up growth remains to be determined.