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Cancer therapeutics-related cardiac dysfunction (CTRCD) has emerged as a major cause of morbidity and mortality in cancer survivors. Effective clinical management of CTRCD is impeded by a lack of sensitive diagnostic and prognostic strategies. Circulating molecular markers could potentially address this need as they are often indicative of cardiac stress before cardiac damage can be detected clinically. A growing understanding of the underlying physiological mechanisms for CTRCD has inspired research efforts to identify novel pathophysiologically relevant biomarkers that may also guide development of cardio-protective therapeutic approaches. The purpose of this review is to evaluate current circulating biomarkers of cardiac stress and their potential role in diagnosis and management of CTRCD. We also discuss some emerging avenues for CTRCD-focused biomarker investigations. [ABSTRACT FROM AUTHOR]

Background and Purpose Axillary web syndrome (AWS) and seroma are common and function-limiting side effects following treatments for breast cancer. Studies of AWS and seroma are rare, and there are no guidelines for physical therapy in these cases. Case Description After left breast lumpectomy due to invasive ductal carcinoma, a 65-year-old female patient underwent intraoperative radiation therapy and whole breast radiation. Seven months later, during treatment for breast swelling, AWS and breast seroma were identified by a physical therapist certified in lymphedema treatment. Treatment goals were to reduce breast swelling and pain and to improve shoulder movements. Interventions included manual lymph drainage, left arm stretching, and instruction about self–lymphatic-drainage and stretching exercise. Also, a compression bra was ordered, and continued daily activities and physical activity were recommended. Outcomes Improvement in shoulder movement, breast swelling, and pain. Discussion Because evidence for treatment guidelines following treatments for breast cancer is lacking, close follow-up for treatment-related complications is recommended. Management should be chosen according to signs and symptoms. Realistic expectations can reduce patient frustration and improve coping strategies and compliance with self-treatment demands. Clinical studies to support these conclusions are required. [ABSTRACT FROM AUTHOR]

Apple processing results in peel, stem, seeds, and pulp being left as a waste product known as apple pomace. This review comprehensively assessed apple pomace composition for nutritional value and bioactive substances and evaluated potential health benefits and safety. Apple pomace is a rich source of health-benefitting nutrients, including minerals, dietary fiber, antioxidants, and ursolic acid, which suggests it has potential use as a dietary supplement, functional food, and/or food additive. Preclinical studies have found apple pomace and its isolated extracts improved lipid metabolism, antioxidant status, and gastrointestinal function and had a positive effect on metabolic disorders (eg, hyperglycemia, insulin resistance, etc.). Safety studies have shown apple pomace to be a safe livestock feed additive and to have pesticide concentrations within safety thresholds established for human consumption. Commercial development of apple pomace for human consumption requires more research focusing on standardized methods of nutrient reporting, mechanistic studies, and human clinical trials. [ABSTRACT FROM AUTHOR]

OBJECTIVES Transapical off-pump mitral valve intervention with neochordae implantation is a novel, minimally invasive procedure for treatment of degenerative mitral valve regurgitation. The aim of this study was to apply control charts (CUSUM curves) to monitor the performance of NeoChord repair during the initial phase of its adoption. METHODS The first 112 consecutive patients who underwent NeoChord repair at our institution between November 2013 and March 2016 were included in the analysis. Mitral Valve Academic Research Consortium criteria for 1-year patient success was utilized to determine failed procedures. Control charts had predetermined acceptable and unacceptable failure rates of 5% and 15%, respectively. RESULTS The actual incidence of 1-year-patient failure was 11% (12 of 112 cases), with a cluster of failures within the first 20 cases. The CUSUM analysis demonstrated an initial learning curve; however, the upper boundary (alarm line) was never crossed. The reassurance line was first crossed after 40 procedures and performance remained stable after 49 procedures. CONCLUSIONS NeoChord repair is a safe procedure, and the results are maintained through the 1-year follow-up. A relative high number of implants were required to overcome the learning curve at our institution due to the concurrent development of patient selection criteria and the technical refinement of the procedure. Future studies are needed to assess the evolution of the learning curve after the wide adoption of the procedure across European and North American centres. [ABSTRACT FROM AUTHOR]

Uric acid stones account for 10%-15% of all urinary stones. Changes in dietary habits, environment or both can result in the increase of uric acid stones. The formation of uric acid stones is related to hyperuricosuria, low urinary volume and persistently low urinary pH. Diabetes and obesity also significantly increase the risk of stone formation. Dual-energy CT provides a convenient and reliable method for diagnosis. Stone composition analysis and 24-hour urine metabolic evaluations should be considered for further evaluation. Most small uric acid stones (diameter <2 cm) can be treated by pharmacotherapy or extracorporeal shock wave lithotripsy. However, ureteroscopy and other minimally invasive procedures should be reserved for larger stones (diameter ≥2 cm), or patients with concomitant urinary tract obstruction and/or infections. Additionally, adjustment of potential pathophysiologic defects by pharmacotherapy and dietary modification is strongly recommended for the prevention of uric stone recurrence. [ABSTRACT FROM AUTHOR]

Heparin-induced thrombocytopaenia (HIT) is a severe and potentially life-threatening adverse drug reaction. Patients become extremely hypercoagulable, and this can lead to life-threatening and limb-threatening thrombosis with a mortality of 5%-10%. HIT is an antibody-mediated process in which platelet activation occurs. Diagnosis requires a high index of suspicion along with a scoring system and laboratory testing. Patients suspected of having HIT must not receive any further heparin or low-molecular weight heparin and must be started on an alternative anticoagulant such as argatroban or danaparoid. Fondaparinux may also be considered but is not licenced for this indication. [ABSTRACT FROM AUTHOR]

OBJECTIVES: Extracorporeal membrane oxygenation (ECMO) transport has not been described in morbidly obese patients, a population that can pose significant challenges in obtaining vascular access, indexed flows and transport logistics. We sought to study the feasibility and safety of transporting obese and morbidly obese patients during extracorporeal support. METHODS: We conducted a retrospective review of all patients transported to our institution while receiving ECMO from September 2008 to September 2016. Survival to decannulation and survival to discharge were the primary outcomes. Obesity and morbid obesity were defined as a body mass index of greater than 30 kg/m2 and greater than 40 kg/m2, respectively. RESULTS: From 2008 to 2016, 222 patients were transported to our institution while receiving ECMO. Among these included patients, 131 were non-obese (interquartile range 22-27 kg/m2), 63 were obese (interquartile range 31-35 kg/m2) and 28 were morbidly obese (interquartile range 41-49 kg/m2), with 6 patients having a body mass index greater than 50 kg/m2 (range 52.3-79 kg/m2). Pre-ECMO arterial blood gases, disease severity indices, cannulation strategies and transport distances were similar between these 3 groups. There was no mortality of patients during transport, and survival to discharge was 66% (n = 87) in non-obese patients, 56% (n = 35) in obese patients and 82% (n = 23) in morbidly obese patients (P = 0.042). On multivariable logistic regression analysis, body mass index was not a predictor of in-hospital mortality (odds ratio 0.99, 95% confidence interval 0.95-1.03; P = 0.517). CONCLUSIONS: Transport of morbidly obese patients receiving ECMO may be performed safely and with excellent results in the setting of a dedicated ECMO transport programme with well-established management protocols. [ABSTRACT FROM AUTHOR]

Background. Electrical stimulation is often used to treat weakness in people with spinal cord injury (SCI); however its efficacy for increasing strength and trophism is weak, and the mechanisms underlying the therapeutic benefits are unknown. Objective. The purpose of this study was to analyze the effects of neuromuscular electrical stimulation (NMES) on muscle function, trophism, and the Akt pathway signaling involved in muscular plasticity after incomplete SCI in rats. Design. This was an experimental study. Methods. Twenty-one adult female Wistar rats were divided into sham, SCI, and SCI plus NMES groups. In injured animals, SCI hemisection was induced by a surgical procedure at the C5-C7 level. The 5-week NMES protocol consisted of biceps brachii muscle stimulation 5 times per week, initiated 48 h after injury. Forepaw function and strength, biceps muscle trophism, and the expression of phosphorylated Akt, p70S6K, and GSK-3β cellular anabolic pathway markers in stimulated muscle tissue were assessed. Results. There was an increase in bicep muscle strength in the NMES group compared with the untreated SCI group, from postoperative day 21 until the end of the evaluation period. Also, there was an increase in muscle trophism in the NMES group compared with the SCI group. Forelimb function gradually recovered in both the SCI group and the NMES group, with no differences between them. Regarding muscle protein expression, the NMES group had higher values for phospho-Akt, phospho-p70S6K, and phospho-GSK-3β than did the SCI group. Limitations. The experimental findings were limited to an animal model of incomplete SCI and may not be fully generalizable to humans. Conclusions. Early cyclical NMES therapy was shown to increase muscle strength and induce hypertrophy after incomplete SCI in a rat model, probably by increasing phospho-Akt, phospho-p70S6K, and phospho-GSK-3β signaling protein synthesis. [ABSTRACT FROM AUTHOR]

Background. The objective was to investigate the long-term development of pain and hyperalgesia after patella fractures. The secondary objective was to report the association between tibiofemoral and patellofemoral osteoarthritis, pain and hyperalgesia. Methods. The study used a cohort design. Patients who were treated for patella fractures between January 2006 and December 2009 were identified. Patients age 20 to 78 years were included. The main outcome was the pain pressure threshold (PPT). Moreover, visual analog scale (VAS) for pain, radiological outcomes of patellofemoral and tibiofemoral osteoarthritis and the pain subscale of the WOMAC and EQ-5D questionnaires were used. Results. Forty-nine patients were included, with a mean age of 53.9 years and a mean follow-up time of 8.5 years. The injured knee region showed significantly decreased PPT levels (P< 0.046), but decreases in PPT were not found for the forearm region (P50.24). The VAS score for the worst pain during the last 24 hours was reported, with a mean of 2.9 6 2.4 cm. The EQ-5D-5L-pain scale was reported, with a mean score of 2.4 (95% confidence interval [CI] 5 2.0-2.7). The WOMAC Pain score was reported, with a mean score of 3.9 (95% CI52.8- 4.9). Moderate correlations were found between the VAS scores and PPT levels (R50.428, P50.002). Weak correlations were found between VAS scores and PPT levels for site 7 (forearm; R50.313, P50.03). Conclusions. The present study suggests that longlasting local hyperalgesia following a patella fracture is common. No side-to-side difference at the forearms were observed, indicating that the observed local hyperalgesia was not part of a generalized sensitization. [ABSTRACT FROM AUTHOR]

Auxin is essential for various aspects of plant development, and modulation of auxin pathways has great potential for crop improvement. Although the current understanding of auxin biology including auxin biosynthesis, transport, and signaling mainly originated from studies in Arabidopsis, several key auxin genes were first discovered in rice, indicating that it is useful to employ several plant systems for auxin research. In this review, we summarize the recent advances in auxin biology in rice, highlight the main contributions of rice research to auxin biology, and discuss the potential for crop improvement through modulating auxin pathways. [ABSTRACT FROM AUTHOR]

Objectives Whole plants of Boerhavia diffusa L. are widely used medicine in Ghana and other tropical countries, for the treatment of wounds and other ailments. The aim of the study was to determine the ability of sequential extracts of B. diffusa to influence oxidation and wound closure in myoblast cells in vitro. Methods Sequential extracts were prepared from the whole plant using four solvents of increasing polarity (hexane, ethyl acetate, methanol and water). Cytotoxicity was determined using the sulforhodamine B staining assay, phase-contrast microscopy, plas DIC microscopy and live-dead staining. Extracts were tested for their ability to reduce 2,2′-azobis(2-amidinopropane) dihydrochloride ( AAPH)-induced oxidation and mediate cell migration after artificial wound generation in C2C12 myoblast cells using the scratch wound assay. Key findings All extracts indicated negligible cytotoxicity ( IC50 > 100 μg/ml), and microscopic evaluation showed no difference from negative controls. AAPH induced a 2.87-fold increase in reactive oxygen species compared to the negative control. Pretreatment with 100 μg/ml of the extracts reduced AAPH-induced oxidation to 1.70-fold of the untreated controls ( P < 0.001). Wound closures in the methanol and water extract treatments were 18.08% and 20.76% higher than the negative control, respectively ( P < 0.01). Conclusions These findings indicate that the hexane, methanol and water extracts of B. diffusa whole plant promote artificial wound healing and protection against oxidation in vitro and therefore warrant further research into its mechanisms of wound healing. [ABSTRACT FROM AUTHOR]

Background: Clostridium difficile, a spore-forming Gram-positive anaerobic bacillus, is the most common causative agent of healthcare-associated diarrhoea. Formation of biofilms may protect C. difficile against antibiotics, potentially leading to treatment failure. Furthermore, bacterial spores or vegetative cells may linger in biofilms in the gut causing C. difficile infection recurrence.Objectives: In this study, we evaluated and compared the efficacy of four antibiotics (fidaxomicin, surotomycin, vancomycin and metronidazole) in penetrating C. difficile biofilms and killing vegetative cells.Methods: C. difficile biofilms grown initially for 48 or 72 h using the colony biofilm model were then treated with antibiotics at a concentration of 25 × MIC for 24 h. Vegetative cells and spores were enumerated. The effect of treatment on biofilm structure was studied by scanning electron microscopy (SEM). The ability of fidaxomicin and surotomycin to penetrate biofilms was studied using fluorescently tagged antibiotics.Results: Both surotomycin and fidaxomicin were significantly more effective than vancomycin or metronidazole (P < 0.001) at killing vegetative cells in established biofilms. Fidaxomicin was more effective than metronidazole at reducing viable spore counts in biofilms (P < 0.05). Fluorescently labelled surotomycin and fidaxomicin penetrated C. difficile biofilms in < 1 h. After 24 h of treatment, SEM demonstrated that both fidaxomicin and surotomycin disrupted the biofilm structure, while metronidazole had no observable effect.Conclusions: Fidaxomicin is effective in disrupting C. difficile biofilms, killing vegetative cells and decreasing spore counts. [ABSTRACT FROM AUTHOR]

Background: Nutritional supplementation and physical activity have been shown to positively influence muscle mass and strength in older adults. The efficacy of long-term nutritional supplementation in combination with physical activity in older adults remains unclear.Methods: Mobility-limited (short physical performance battery [SPPB] ≤9) and vitamin D insufficient (serum 25(OH) D 9-24 ng/mL) older adults were recruited for this study. All subjects participated in a physical activity program. Subjects were randomized to consume a daily nutritional supplement (150 kcal, 20 g whey protein, 800 IU vitamin D, 119 mL beverage) or placebo (30 kcal, nonnutritive, 119 mL). In a prespecified secondary analysis, we examined total-body composition (dual energy X-ray absorptiometry), thigh composition (computed tomography), and muscle strength, power, and quality before and after the 6-month intervention.Results: One hundred and forty-nine subjects were randomized into the study [mean (standard deviation, SD) age 78.5 (5.4) years; 46.3% female; mean (SD) short physical performance battery 7.9 (1.2); mean (SD) vitamin D 18.7 (6.4) ng/mL]. After the intervention period both groups demonstrated improvements in muscle strength, body composition, and thigh composition. Nutritional supplementation lead to further losses of intermuscular fat (p = .049) and increased normal muscle density (p = .018).Conclusions: Six months of physical activity resulted in improvements in body composition, subcutaneous fat, intermuscular fat, and strength measures. The addition of nutritional supplementation resulted in further declines in intermuscular fat and improved muscle density compared to placebo. These results suggest nutritional supplementation provides additional benefits to mobility-limited older adults undergoing exercise training. ClinicalTrials.gov Identifier: NCT01542892. [ABSTRACT FROM AUTHOR]

Background: Clostridium difficile is the most common cause of hospital-acquired infections, responsible for >450000 infections annually in the USA. Probiotics provide a promising, well-tolerated adjunct therapy to standard C. difficile infection (CDI) treatment regimens, but there is a paucity of data regarding their effectiveness for the treatment of an initial CDI.Objectives: We conducted a pilot randomized controlled trial of 33 participants from February 2013 to February 2015 to determine the feasibility and health outcomes of adjunct probiotic use in patients with an initial mild to moderate CDI.Methods: The intervention was a 28 day, once-daily course of a four-strain oral probiotic capsule containing Lactobacillus acidophilus NCFM, Lactobacillus paracasei Lpc-37, Bifidobacterium lactis Bi-07 and B. lactis Bl-04. The control placebo was identical in taste and appearance. Registered at clinicaltrials.gov: trial registration number = NCT01680874.Results: Probiotic adjunct therapy was associated with a significant improvement in diarrhoea outcomes. The primary duration of diarrhoea outcome (0.0 versus 1.0 days; P = 0.039) and two exploratory outcomes, total diarrhoea days (3.5 versus 12.0 days; P = 0.005) and rate of diarrhoea (0.1 versus 0.3 days of diarrhoea/stool diary days submitted; P = 0.009), all decreased in participants with probiotic use compared with placebo. There was no significant difference in the rate of CDI recurrence or functional improvement over time between treatment groups.Conclusions: Probiotics are a promising adjunct therapy for treatment of an initial CDI and should be further explored in a larger randomized controlled trial. [ABSTRACT FROM AUTHOR]

Background: Norovirus is the leading cause of community-acquired and nosocomial acute gastroenteritis. Routine testing for norovirus is seldom undertaken, and diagnosis is mainly based on presenting symptoms. This makes understanding the burden of medically attended norovirus-attributable gastroenteritis (MA-NGE) and targeting care and prevention strategies challenging.Methods: We used linked population-based healthcare datasets (Clinical Practice Research Datalink General Practice OnLine Database linked with Hospital Episode Statistics Admitted Patient Care) to model the incidence of MA-NGE associated with primary care consultations or hospitalizations according to age groups in England in the period July 2007-June 2013.Results: Mean annual incidence rates of MA-NGE were 4.9/1000 person-years and 0.7/1000 person-years for episodes involving primary care or hospitalizations, respectively. Incidence rates were highest in children aged <5 years: 34.0 consultations/1000 person-years and 3.3 hospitalizations/1000 person-years. Medically attended norovirus-attributable gastroenteritis hospitalization rates were second highest in adults aged >65 years (1.7/1000 person-years).Conclusions: In this particular study, the burden of MA-NGE estimated from healthcare datasets was higher than previously estimated in small cohort studies in England. Routinely collected primary care and hospitalization datasets are useful resources to estimate and monitor the burden of MA-NGE in a population over time. [ABSTRACT FROM AUTHOR]

Exercise is associated with unequivocal health benefits and results in many structural and functional changes of the myocardium that enhance performance and prevent heart failure. However, intense exercise also presents a significant hemodynamic challenge in which the right-sided heart chambers are exposed to a disproportionate increase in afterload and wall stress that can manifest as myocardial fatigue or even damage if intense exercise is sustained for prolonged periods. This review focuses on the physiological factors that result in a disproportionate load on the right ventricle during exercise and the long-term consequences. The changes in cardiac structure and function that define 'athlete's heart' disproportionately affect the right-sided heart chambers and this can raise important diagnostic overlap with some cardiac pathologies, particularly some inherited cardiomyopathies. The interaction between exercise and arrhythmogenic right ventricular cardiomyopathy (ARVC) will be highlighted as an important example of how hemodynamic stressors can combine with deficiencies in cardiac structural elements to cause cardiac dysfunction predisposing to arrhythmias. The extent to which extreme exercise can cause adverse remodelling in the absence of a genetic predisposition remains controversial. In the athlete with profound changes in heart structure, it can be extremely challenging to determine whether common symptoms such as palpitations may be a marker of more sinister arrhythmias. This review discusses some of the techniques that have recently been proposed to identify pathology in these circumstances. Finally, we will discuss recent evidence defining the role of exercise restriction as a therapeutic intervention in individuals predisposed to arrhythmogenic cardiomyopathy. [ABSTRACT FROM AUTHOR]

Right ventricular (RV) dysfunction is a strong predictor of outcome in heart failure and is a key determinant of exercise capacity. Despite these crucial findings, the RV remains understudied in the clinical, experimental, and computer modelling literature. This review outlines how recent advances in using computer modelling and cardiac imaging synergistically help to understand RV function in health and disease. We begin by highlighting the complexity of interactions that make modelling the RV both challenging and necessary, and then summarize the multiscale modelling approaches used to date to simulate RV pump function in the context of these interactions. We go on to demonstrate how these modelling approaches in combination with cardiac imaging have improved understanding of RV pump function in pulmonary arterial hypertension, arrhythmogenic right ventricular cardiomyopathy, dyssynchronous heart failure and cardiac resynchronization therapy, hypoplastic left heart syndrome, and repaired tetralogy of Fallot. We conclude with a perspective on key issues to be addressed by computational models of the RV in the near future. [ABSTRACT FROM AUTHOR]

Right ventricular failure predicts adverse outcome in patients with pulmonary hypertension (PH), and in subjects with left ventricular heart failure and is associated with interstitial fibrosis. This review manuscript discusses the cellular effectors and molecular mechanisms implicated in right ventricular fibrosis. The right ventricular interstitium contains vascular cells, fibroblasts, and immune cells, enmeshed in a collagen-based matrix. Right ventricular pressure overload in PH is associated with the expansion of the fibroblast population, myofibroblast activation, and secretion of extracellular matrix proteins. Mechanosensitive transduction of adrenergic signalling and stimulation of the renin–angiotensin–aldosterone cascade trigger the activation of right ventricular fibroblasts. Inflammatory cytokines and chemokines may contribute to expansion and activation of macrophages that may serve as a source of fibrogenic growth factors, such as transforming growth factor (TGF)-b. Endothelin-1, TGF-bs, and matricellular proteins co-operate to activate cardiac myofibroblasts, and promote synthesis of matrix proteins. In comparison with the left ventricle, the RV tolerates well volume overload and ischemia; whether the right ventricular interstitial cells and matrix are implicated in these favourable responses remains unknown. Expansion of fibroblasts and extracellular matrix protein deposition are prominent features of arrhythmogenic right ventricular cardiomyopathies and may be implicated in the pathogenesis of arrhythmic events. Prevailing conceptual paradigms on right ventricular remodelling are based on extrapolation of findings in models of left ventricular injury. Considering the unique embryologic, morphological, and physiologic properties of the RV and the clinical significance of right ventricular failure, there is a need further to dissect RV-specific mechanisms of fibrosis and interstitial remodelling. [ABSTRACT FROM AUTHOR]

Speech, language, and music are defining characteristics of humans. Recent advances in neuroimaging have allowed researchers to examine brain activity during speech and language tasks, revealing the complexity of these processes. Research has also begun to better understand the neurobiological underpinnings of speech and language impairments. Yet, there remains a need to better understand how music therapy impacts these impairments. The main purpose of this manuscript is to provide an overview of the neuroscience of speech and language. The use of music therapy in the treatment of speech and language impairments, such as aphasia and dysarthria, will also be touched upon. The neuroscience of auditory processing, language processing, and speech production will be provided, followed by a brief overview of the neural underpinnings of dysarthria and aphasia and implications for music therapy. [ABSTRACT FROM AUTHOR]

Background: Standard cardiopulmonary resuscitation (CPR) is ineffective in treating traumatic cardiac arrest (TCA) following hemorrhagic shock despite fluid resuscitation. CPR adjuncts, including abdominal compressions and external counter pressure, have shown some success in laboratory settings. The Abdominal Aortic and Junctional Tourniquet (AAJT) is a device that occludes both venous and arterial blood at the level of the aortic bifurcation and likely increases thoracic pressure when applied to the abdomen. We developed a swine model of controlled hemorrhage to induce a state of TCA to test the ability of the AAJT to improve the efficacy of CPR.Methods: Twelve splenectomized, Yorkshire, male swine (70-90 kg) were randomized into two groups: presence or absence of AAJT placement. Controlled hemorrhage was performed at a rate of 2 mL/kg/min until systolic blood pressure reached below 10 mm Hg (defined as cardiac arrest). Following 3 minutes of arrest, the animals underwent CPR using a mechanical compression device along with either the presence or absence of the AAJT. Concurrently, 5 units of whole blood (2,500 mL) were delivered through the jugular vein at 500 mL/min. Efficacy of CPR was assessed by analyzing rates of return of spontaneous circulation (ROSC) and survival. Blood pressure, carotid blood flow, and other hemodynamic values were also compared.Findings: No significant differences between groups were observed before treatments. The controlled hemorrhage resulted in an average loss of 2,654 ± 323 g of blood over 18.2 ± 3.9 minutes. All animals that had a ROSC survived to the end of the 1-hour observation period. Animals with AAJT survived 83% (5/6) compared to 17% (1/6) of animals without AAJT. Finally, blood pressure, carotid flow, mean pulmonary artery pressure, and end tidal carbon dioxide were all significantly different between groups at the end of the first 10-minute compression period.Discussion/impact/recommendations: These results suggest that the AAJT could allow for increased CPR efficacy in cases of TCA when used in conjunction with rapid, massive blood transfusions. [ABSTRACT FROM AUTHOR]

Objectives: To determine the susceptibility to colistin of Hafnia alvei and Hafnia paralvei, and to compare methods for colistin resistance detection in the Hafnia genus.Methods: A collection of 25 Hafnia isolates was studied. Species were identified by using 16S rRNA gene sequencing with subsequent phylogeny analysis. Susceptibility to colistin was determined using the broth microdilution (BMD) reference method, the Phoenix automated system, the Rapid Polymyxin NP test, the Etest system and the disc diffusion method.Results: The collection consisted of 15 H. alvei and 10 H. paralvei isolates. Based on the 16S rRNA analysis, a close relationship of the Hafnia genus with naturally colistin-resistant enterobacterial genera (Proteus, Morganella, Providencia and Serratia) was identified. Susceptibility testing performed using the BMD method, the Phoenix automated system and the Rapid Polymyxin NP test revealed a high rate of colistin resistance (96%). Underestimation of colistin resistance using Etest strips (72%) and the disc diffusion method (0%) was observed.Conclusions: The high rate of colistin resistance observed within the Hafnia genus and its close phylogenetic relationship with naturally colistin-resistant genera suggest that Hafnia is a naturally colistin-resistant enterobacterial genus. [ABSTRACT FROM AUTHOR]

Objectives: To evaluate potential anti-biofilm agents for their ability to enhance the activity of antibiotics for local treatment of localized biofilm infections.Methods: Staphylococcus aureus and Pseudomonas aeruginosa in vitro biofilm models were developed. The putative antibiotic enhancers N-acetylcysteine, acetylsalicylic acid, sodium salicylate, recombinant human deoxyribonuclease I, dispersin B, hydrogen peroxide and Johnson's Baby Shampoo (JBS) were tested for their anti-biofilm activity alone and their ability to enhance the activity of antibiotics for 7 or 14 days, against 5 day old biofilms. The antibiotic enhancers were paired with rifampicin and clindamycin against S. aureus and gentamicin and ciprofloxacin against P. aeruginosa. Isolates from biofilms that were not eradicated were tested for antibiotic resistance.Results: Antibiotic levels 10× MIC and 100× MIC significantly reduced biofilm, but did not consistently eradicate it. Antibiotics at 100× MIC with 10% JBS for 14 days was the only treatment to eradicate both staphylococcal and pseudomonal biofilms. Recombinant human deoxyribonuclease I significantly reduced staphylococcal biofilm. Emergence of resistance of surviving isolates was minimal and was often associated with the small colony variant phenotype.Conclusions: JBS enhanced the activity of antibiotics and several other promising anti-biofilm agents were identified. Antibiotics with 10% JBS eradicated biofilms produced by both organisms. Such combinations might be useful in local treatment of localized biofilm infections. [ABSTRACT FROM AUTHOR]

Objectives: To determine natural phenotypic susceptibility of non-group M HIV-1 to integrase strand transfer inhibitors (INSTIs) in a large panel of 39 clinical strains from groups O, N and P and to identify genotypic polymorphisms according to susceptibility levels.Methods: Susceptibility to raltegravir, elvitegravir and dolutegravir was evaluated in 36 HIV-1/O, 2 HIV-1/N and 1 HIV-1/P strains plus an HIV-1/M reference strain. IC50 values were determined after 3 days, and fold changes (FCs) were calculated relative to the HIV-1/M strain. Genotypic polymorphism was determined by amplification of codons 19-263 of the integrase; the natural occurrence of resistance-associated mutations was analysed using the main resistance algorithms and the IAS-USA list. VESPA analysis of the strain sequences was used to determine a signature pattern associated with higher FC.Results: Similar IC50 results were observed for the three drugs. Based on the value for the HIV-1/M reference strain, the data showed FC values <2.5 for raltegravir and dolutegravir, whereas the distribution for elvitegravir was heterogeneous, with FC > 10 for six strains (15%). Analysis of the non-M integrase sequences showed a high level of polymorphism without a major genotypic impact; it also revealed mutations that may be associated with the highest FC values obtained for elvitegravir.Conclusions: Our phenotypic data showed that non-M strains are globally susceptible to the three currently used INSTIs, but the impact of the high FC values observed for some strains with elvitegravir needs to be explored. Clinical data are now needed to confirm these phenotypic results. [ABSTRACT FROM AUTHOR]

A continuous isoelectric electroencephalogram reflects an interruption of endogenously-generated activity in cortical networks and systematically results in a complete dissolution of conscious processes. This electro-cerebral inactivity occurs during various brain disorders, including hypothermia, drug intoxication, long-lasting anoxia and brain trauma. It can also be induced in a therapeutic context, following the administration of high doses of barbiturate-derived compounds, to interrupt a hyper-refractory status epilepticus. Although altered sensory responses can be occasionally observed on an isoelectric electroencephalogram, the electrical membrane properties and synaptic responses of individual neurons during this cerebral state remain largely unknown. The aim of the present study was to characterize the intracellular correlates of a barbiturate-induced isoelectric electroencephalogram and to analyse the sensory-evoked synaptic responses that can emerge from a brain deprived of spontaneous electrical activity. We first examined the sensory responsiveness from patients suffering from intractable status epilepticus and treated by administration of thiopental. Multimodal sensory responses could be evoked on the flat electroencephalogram, including visually-evoked potentials that were significantly amplified and delayed, with a high trial-to-trial reproducibility compared to awake healthy subjects. Using an analogous pharmacological procedure to induce prolonged electro-cerebral inactivity in the rat, we could describe its cortical and subcortical intracellular counterparts. Neocortical, hippocampal and thalamo-cortical neurons were all silent during the isoelectric state and displayed a flat membrane potential significantly hyperpolarized compared with spontaneously active control states. Nonetheless, all recorded neurons could fire action potentials in response to intracellularly injected depolarizing current pulses and their specific intrinsic electrophysiological features were preserved. Manipulations of the membrane potential and intracellular injection of chloride in neocortical neurons failed to reveal an augmented synaptic inhibition during the isoelectric condition. Consistent with the sensory responses recorded from comatose patients, large and highly reproducible somatosensory-evoked potentials could be generated on the inactive electrocorticogram in rats. Intracellular recordings revealed that the underlying neocortical pyramidal cells responded to sensory stimuli by complex synaptic potentials able to trigger action potentials. As in patients, sensory responses in the isoelectric state were delayed compared to control responses and exhibited an elevated reliability during repeated stimuli. Our findings demonstrate that during prolonged isoelectric brain state neurons and synaptic networks are dormant rather than excessively inhibited, conserving their intrinsic properties and their ability to integrate and propagate environmental stimuli. [ABSTRACT FROM AUTHOR]

Background: Single low-dose primaquine (PQ) reduces Plasmodium falciparum infectivity before it impacts gametocyte density. Here, we examined the effect of PQ on gametocyte sex ratio as a possible explanation for this early sterilizing effect.Methods: Quantitative reverse-transcription polymerase chain reaction assays were developed to quantify female gametocytes (targeting Pfs25 messenger RNA [mRNA]) and male gametocytes (targeting Pf3D7_1469900 mRNA) in 2 randomized trials in Kenya and Mali, comparing dihydroartemisinin-piperaquine (DP) alone to DP with PQ. Gametocyte sex ratio was examined in relation to time since treatment and infectivity to mosquitoes.Results: In Kenya, the median proportion of male gametocytes was 0.33 at baseline. Seven days after treatment, gametocyte density was significantly reduced in the DP-PQ arm relative to the DP arm (females: 0.05% [interquartile range {IQR}, 0.0-0.7%] of baseline; males: 3.4% [IQR, 0.4%-32.9%] of baseline; P < .001). Twenty-four hours after treatment, gametocyte sex ratio became male-biased and was not significantly different between the DP and DP-PQ groups. In Mali, there was no significant difference in sex ratio between the DP and DP-PQ groups (>0.125 mg/kg) 48 hours after treatment, and gametocyte sex ratio was not associated with mosquito infection rates.Conclusions: The early sterilizing effects of PQ may not be explained by the preferential clearance of male gametocytes and may be due to an effect on gametocyte fitness. [ABSTRACT FROM AUTHOR]

A Glu–Phe (EF) was isolated from onion (Allium cepaL. cv. Sunpower). The chemical structure of EF was determined by nuclear magnetic resonance and electrospray ionization–mass (ESI−MS) spectroscopy. We showed that EF reduced lipid accumulation in mouse hepatocytes by inhibiting the expression of sterol regulatory element-binding protein-1c (SREBP–1c) and its lipogenic target genes. We also found that AMP-activated protein kinase (AMPK) was required for the inhibitory effect of EF on lipid accumulation in mouse hepatocytes. Furthermore, EF was qualified in nine onion cultivars by selective multiple reaction-monitoring detection of liquid chromatography–ESI−MS. These results suggest that EF could contribute to the beneficial effect of onion supplement in maintaining hepatic lipid homeostasis. EFfrom onion decreases the expression of SREBP-1c and its lipogenic target genes through activating AMP-AMPK, thereby attenuating lipid accumulation in mouse hepatocytes. [ABSTRACT FROM PUBLISHER]

Background. Increasing azithromycin usage and resistance in Neisseria gonorrhoeae threatens current dual treatment. Because antimicrobial exposure influences resistance, we analyzed the association between azithromycin exposure and decreased susceptibility of N. gonorrhoeae. Methods. We included N. gonorrhoeae isolates of patients who visited the Amsterdam STI Clinic between 1999 and 2013 (t0), with another clinic visit in the previous 60 days (t-1). Exposure was defined as the prescription of azithromycin at t-1. Using multivariable linear regression, we assessed the association between exposure and azithromycin minimum inhibitory concentration (MIC). Whole genome sequencing (WGS) was performed to produce a phylogeny and identify multilocus sequence types (MLST), N. gonorrhoeae multiantigen sequence types (NG-MAST), and molecular markers of azithromycin resistance. Results. We included 323 isolates; 212 were unexposed to azithromycin, 14 were exposed =30 days, and 97 were exposed between 31 and 60 days before isolation. Mean azithromycin MIC was 0.28 mg/L (range, <0.016-24 mg/L). Linear regression adjusted for age, ethnicity, infection site, and calendar year showed a significant association between azithromycin exposure =30 days and MIC (β, 1.00; 95% confidence interval, 0.44-1.56; P = .002). WGS was performed on 31 isolates: 14 unexposed, 14 exposed to azithromycin ≥30 days before isolation, and 3 t-1 isolates. Exposure to azithromycin was significantly associated with A39T or G45D mtrR mutations (P = .046) but not with MLST or NG-MAST types. Conclusions. The results suggest that frequent azithromycin use in populations at high risk of contracting N. gonorrhoeae induces an increase in MIC and may result in resistance. [ABSTRACT FROM AUTHOR]

BACKGROUND There are no comprehensive guidelines on management of hypertensive emergency (HTNE) and complications. Despite advances in antihypertensive medications HTNE is accompanied with significant morbidity and mortality. METHODS We queried the 2002-2012 nationwide inpatient sample database to identify patients with HTNE. Trends in incidence of HTNE and in-hospital mortality were analyzed. Logistic regression analysis was used to assess the relationship between end-organ complications and in-hospital mortality. RESULTS Between 2002 and 2012, 129,914 admissions were included. Six hundred and thirty (0.48%) patients died during their hospital stay. There was an increase in the number of HTNE admissions (9,511-15,479; Ptrend < 0.001) with concurrent reduction of in-hospital mortality (0.8-0.3%; Ptrend < 0.001) by the year 2012 compared to 2002. Patients who died during hospitalization were older, had longer length of stay, higher cost of stay, more comorbidities, and higher risk scores. Presence of acute cardiorespiratory failure [adjusted odds ratio (OR), 15.8; 95% confidence interval (CI), 13.2-18.9], stroke or transient ischemia attack (TIA) (adjusted OR, 7.9; 95% CI, 6.3-9.9), chest pain (adjusted OR, 5.9; 95% CI, 4.4-7.7), stroke/TIA (adjusted OR, 5.9; 95% CI, 4.5-7.7), and aortic dissection (adjusted OR, 5.9; 95% CI, 2.8-12.4) were most predictive of higher in-hospital mortality in addition to factors such as age, aortic dissection, acute myocardial infarction, acute renal failure, and presence of neurological symptoms. CONCLUSION A rising trend in hospitalization for HTNE, with an overall decrease in in-hospital mortality was observed from 2002 to 2012, possibly related to changes in coding practices and improved management. Presence of acute cardiorespiratory failure, stroke/TIA, chest pain, and aortic dissection were most predictive of higher hospital mortality. [ABSTRACT FROM AUTHOR]

Background: Patients in whom a diagnosis of pulmonary embolism (PE) is suspected and whose D-dimers are elevated frequently require CT pulmonary angiogram (CTPA) for diagnosis. Because D-dimer rises with age, an age-adjusted D-dimer threshold may prevent unnecessary radiation exposure from CTPA in older patients.Objective: To determine the efficacy and safety of implementing an age-adjusted D-dimer threshold to exclude PE.Design, Settings and Patients: Retrospective comparison of conventional and age-adjusted D-dimer thresholds in 1000 consecutive patients who had both D-dimer and CTPA.Main Outcome Measures: Conventional and age-adjusted D-dimer thresholds for excluding PE were <250 ng/mL and 5× age for patients older than 50 years, respectively. We defined patients as unlikely to have PE using the revised Geneva score (RGS) and two different categories of clinical risk: RGS ≤5 and RGS ≤10.Results: We diagnosed PE by CTPA in 244 (24.4%) patients. 3/86 patients (3.5%) whose D-dimer was below the conventional threshold of 250 ng/mL had PE (RGS 3, 9 and 14), all of which were judged to be light clot load (group 1). 3/108 patients (2.8%) whose D-dimer lay between 250 ng/mL and the age-adjusted threshold had PE (RGS 6, 8 and 9), all of which were again judged to be light clot load (group 2). 62/108 group 2 patients with RGS ≤5 were considered unlikely to have PE as were 102/108 using the RGS clinical risk category ≤10. None of the 62 patients with RGS ≤5 had PE while 3/102 patients with RGS ≤10 had PE. 236/806 patients (29.3%) whose D-dimer was above the age-adjusted threshold had PE (group 3).Conclusions: In a consecutive series of 1000 patients, an RGS ≤5 and an age-adjusted D-dimer would have led to 62 fewer CTPA at a cost of no missed PEs. [ABSTRACT FROM AUTHOR]

OBJECTIVES: To determine the risk of atrioventricular valve failure (valve intervention or moderate or greater regurgitation) during the lifetime of patients with single ventricle physiology and common atrioventricular valve. METHODS: Patients' data were extracted from an existing bi-national, population based registry. A retrospective review of their medical records was undertaken to determine the incidence of atrioventricular valve repair/replacement or moderate or greater regurgitation. RESULTS: From a registry of 1468 Fontan survivors, 136 patients with common atrioventricular valve were identified. Complete echocardiographic follow-up was available for 114 patients. Median length of follow-up was 10.2 years (interquartile range 5-15 years). Twentyfive year survival and freedom from Fontan failure were 94% [95% confidence interval (CI), 88-100%] and 74% (95% CI, 64-87%), respectively. Twenty-eight patients underwent 24 initial repairs and 4 replacements. The 24 patients undergoing repair subsequently needed 6 rerepairs, 2 replacements and 8 had moderate or greater regurgitation at last follow-up. Four-year freedom from atrioventricular valve repair failure was 50% (95% CI, 34-75%). An additional 30 patients developed moderate or greater atrioventricular valve regurgitation (6 New York Heart Association >3, 10 Fontan failures, 0 deaths). Cumulative incidence of the composite endpoint of atrioventricular valve failure at 28 years was 62% (95% CI, 49-74%). CONCLUSIONS: Patients with single ventricle physiology and common atrioventricular valve experience a continuous decline in valve function. The majority of patients experience valve failure in the first 30 years of life. [ABSTRACT FROM AUTHOR]

One of the major barriers to the successful design and implementation of human immunodeficiency virus (HIV) curative strategies is the limited ability to sensitively, specifically, and precisely quantify and characterize the whole-body burden of replication-competent HIV in individuals on effective antiretroviral therapy. Here, we review the development and validation of assays that directly and indirectly measure the size and distribution of the reservoir in blood and tissues. We also discuss the role that treatment interruptions will have in validating these assays and ultimately as a "proof of cure." [ABSTRACT FROM AUTHOR]

The uneven anatomic distribution of cell subsets that harbor human immunodeficiency virus (HIV) during antiretroviral therapy (ART) complicates investigation of the barriers to HIV cure. Here we propose that while previous studies done largely in blood cells have led to important investigations into HIV latency, other important mechanisms of HIV persistence during ART may not be readily apparent in the bloodstream. We specifically consider as an example the question of ongoing HIV replication during ART. We discuss how growing understanding of key anatomic sanctuaries for the virus can inform future experiments aimed at further clarifying this issue. [ABSTRACT FROM AUTHOR]

Human immunodeficiency virus (HIV) type 1 uses the CD4 molecule as its principal receptor to infect T cells. HIV-1 integrates its viral genome into the host cell, leading to persistent infection wherein HIV-1 can remain transcriptionally silent in latently infected CD4+ T cells. On reactivation of replication-competent provirus, HIV-1 envelope glycoproteins (Env) are expressed and accumulate on the cell surface, allowing infected cells to be detected and targeted by endogenous immune responses or immune interventions. HIV-1 Env-specific antibodies have the potential to bind HIV-1 cell surface Env and promote elimination of infected CD4+ T cells by recruiting cytotoxic effector cells, such as natural killer cells, monocytes, and polymorphonuclear cells. Harnessing humoral and innate cellular responses has become one focus of research to develop innovative strategies to recruit and redirect cytotoxic effector cells to eliminate the HIV-1 latently infected CD4+ T-cell reservoir. [ABSTRACT FROM AUTHOR]

The effect of experimentally increasing the postpartum protein supply on plasma protein synthesis, rumen tissue proliferation, and immune homeostasis was studied using 8 periparturient Holstein cows in a complete randomized design. At calving, cows were assigned to abomasal infusion of water (CTRL) or casein (CAS) in addition to a lactation diet. Casein infusion was gradually decreased from 696 ± 1 g/d at +2 d relative to calving (DRTC) to 212 ± 10 g/d at +29 DRTC to avoid excessive supply. Synthesis rate of plasma proteins was measured at -14, +4, +15, and +29 DRTC by measuring [13C]Phe isotopic enrichment in arterial plasma free Phe, total plasma proteins, and albumin after 3, 5, and 7 h of jugular ring[13C]Phe infusion. Plasma volume was determined at +4 and +29 DRTC by dilution of a [125I]BSA dose. Synthesis rate of tissue protein in biopsied rumen papillae was determined by measuring [13C]Phe isotopic enrichment, and mRNA expression of selected genes was measured by real-time qPCR. Total and differential leukocyte counts were performed and immune responsiveness of monocytes was evaluated by tumor necrosis factor α (TNFα) concentration on ex vivo whole blood stimulation with Escherichia coli lipopolysaccharide (LPS) and responsiveness of T-lymphocytes by interferon β (IFNβ) concentration on stimulation with Staphylococcus aureus enterotoxin ß (SEB). Further, ELISA plasma concentrations of IgM, IgA, and IgG were determined. The DRTC affected the majority of investigated parameters as expected. The CAS treatment increased milk protein yield (P = 0.04), and tended to lower TNFα (P = 0.06), and lowered IFNβ (P = 0.03) responsiveness per monocyte and lymphocyte, respectively, compared with CTRL. Further, fractional synthesis rate of albumin was greater at +4 DRTC for CAS compared with CTRL but did not differ by +29 DRTC (interaction: P = 0.01). In rumen papillae, synthesis rate of tissue protein was greater for CAS compared with CTRL (P < 0.01) and mRNA expression of genes for cell proliferation tended to be or were greater for CAS compared with CTRL (P ≤ 0.07). In conclusion, increased postpartum protein supply seem to enhance vital body functions as interpreted from increased liver synthesis of albumin, increased rumen papillae proliferation, and stabilized the ex vivo inflammatory responsiveness of leukocytes. Further studies are needed to enlighten the importance of increased postpartum protein supply in periparturient cows. [ABSTRACT FROM AUTHOR]

We performed 2 experiments to study the effects of supplementing sow diets with Saccharomyces cerevisiae refermented sorghum dried distiller's grains with solubles (SSDDGS) from late gestation to weaning on the performance of sows and their progeny. In Exp. 1, 24 sows at 85 d of gestation were allocated to the following 3 dietary treatments: 1) sows fed a basal diet from late gestation to weaning (n = 8), 2) sows fed a diet with 2% SSDDGS (n = 8), and 3) sows fed a diet with 4% SSDDGS (n = 8). The 4% SSDDGS treatment significantly improved the sows' ADFI, the litter weaning alive rate, and the individual piglet weaning weights and significantly reduced the litter stillbirth rate and the levels of urea N and somatic cell counts (SCC) in the milk. However, the 2% SSDDGS treatment did not alter the performance of the sows or progeny. Therefore, we considered the volume of 4% SSDDGS to be more efficient than 2% SSDDGS. To verify the results of Exp. 1, we performed Exp. 2, in which 60 sows at 85 d of gestation were allocated into the following 2 dietary treatments: 1) sows fed a basal gestation diet from 85 d of gestation to weaning (n = 30) and 2) sows fed a basal diet with 4% SSDDGS from 85 d of gestation to weaning (n = 30). The 4% SSDDGS supplementation tended to increase the sows' ADFI, litter weaning size, litter weight gain during lactation, and individual piglet weaning weight and weight gain during lactation, and it also increased the milk yield and the fat and DM contents of the milk. This treatment also decreased the levels of urea N and SCC in the milk. Therefore, the present study indicates that supplementing sow diets with 4% SSDDGS from late gestation to weaning has the potential to 1) increase sow ADFI, 2) promote progeny growth performance, 3) increase sow milk production and quality, and 4) improve the maternal health status as indicated by improved protein utilization and reduced potential inflammatory response. [ABSTRACT FROM AUTHOR]

Short-chain fatty acids (SCFAs), mainly acetate, propionate and butyrate, produced by microbial fermentation of undigested food substances are believed to play a beneficial role in human gut health. Short-chain fatty acids influence colonic health through various mechanisms. In vitro and ex vivo studies show that SCFAs have anti-inflammatory and anticarcinogenic effects, play an important role in maintaining metabolic homeostasis in colonocytes and protect colonocytes from external harm. Animal studies have found substantial positive effects of SCFAs or dietary fiber on colonic disease, but convincing evidence in humans is lacking. Most human intervention trials have been conducted in the context of inflammatory bowel disease. Only a limited number of those trials are of high quality, showing little or no favorable effect of SCFA treatment over placebo. Opportunities for future research include exploring the use of combination therapies with anti-inflammatory drugs, prebiotics or probiotics; the use of prodrugs in the setting of carcinogenesis; or the direct application of SCFAs to improve mucosal healing after colonic surgery. [ABSTRACT FROM AUTHOR]

Study Question: What is the clinical association of maternal thyroid function with placental hemodynamic function?Summary Answer: A higher free thyroxine (FT4) concentration in early pregnancy is associated with higher placental vascular resistance.What Is Known Already: Suboptimal placental function is associated with preeclampsia (which, in turn, further deteriorates placental hemodynamics and impairs the fetal blood supply), fetal growth restriction and premature delivery. Studies have suggested that thyroid hormone (TH) has a role in placental development through effects on trophoblast proliferation and invasion.Study Design, Size, Duration: This study was embedded in The Generation R cohort, a population-based prospective study from early fetal life onwards in Rotterdam, the Netherlands. In total, 7069 mothers with expected delivery date between April 2002 and January 2006 were enrolled during early pregnancy.Participants/materials, Setting, Method: Thyroid-stimulating hormone (TSH) and free thyroxine (FT4) concentrations were measured during early pregnancy (median 13.4 weeks, 95% range 9.7-17.6 weeks). Placental function was assessed by Doppler ultrasound via measurement of arterial vascular resistance, i.e. umbilical artery pulsatility index (PI) and uterine artery resistance index (RI) (both measured twice, between 18-25th and after 25th gestational weeks) and the presence of uterine artery notching (once after the 25th gestational week) in 5184 pregnant women.Main Results and the Role Of Chance: FT4 was positively linearly associated with umbilical artery PI in the second and third trimesters as well as with uterine artery RI in the second trimester and the risk of uterine artery notching in the third trimester (P < 0.05 for all). The association of thyroid function with preeclampsia and birth weight was partially mediated through changes in placental function, with the percentages of mediated effects being 10.4% and 12.5%, respectively.Limitations, Reasons For Caution: A potential limitation is the availability of only a single time point for TH measurements and different numbers of missing placental ultrasound measurements for the adverse outcomes.Wider Implications Of the Findings: A higher FT4 concentration in early pregnancy is associated with higher vascular resistance in the second and third trimesters in both the maternal and fetal placental compartment. These effects on placental function might explain the association of FT4 with adverse pregnancy outcomes, including preeclampsia and fetal growth restriction.Study Funding/competing Interest(s): This work was supported by a fellowship from ERAWEB, a project funded by the European Commission (to M.B.) and by clinical fellowship from The Netherlands Organization for Health Research and Development (ZonMw), Project 90700412 (to R.P.P.). The authors have no conflict of interest.Trial Registration Number: N/A. [ABSTRACT FROM AUTHOR]

Background: Animal studies and case reports have suggested that methylphenidate exerts adverse effects on gonadal hormones. This study aimed to determine whether methylphenidate alters testosterone levels in children with attentiondeficit/ hyperactivity disorder through comparison of those with or without methylphenidate treatment. Methods: This 4-week, nonrandomized, prospective study conducted in Taiwan included 203 attention-deficit/hyperactivity disorder patients with a mean age of 8.7 years (boys: 75.8%). After the initial recruitment, 137 received daily methylphenidate treatment (medicated group) and 66 were assessed through naturalistic observation (nonmedicated group). The saliva samples of attention-deficit/hyperactivity disorder patients were used to quantify testosterone levels at baseline and the endpoint by using the chemiluminescence immunoassay. At the 4th week, 86 patients in the medicated group and 46 patients in the nonmedicated group were eligible for statistical analyses. Results: During the study period, salivary testosterone levels did not significantly change in the medicated group (P = .389) or in the nonmedicated group (P = .488). After correction for the potential confounding effects of age and sex, salivary testosterone levels still remained unchanged in the medicated and nonmedicated groups during the 4-week follow-up. In the medicated group, changes in salivary testosterone levels over 4 weeks were not significantly correlated with the methylphenidate daily dose (mean daily dose: 18.1 mg). Conclusions: Findings suggest that short-term treatment with methylphenidate at usual doses does not significantly alter salivary testosterone levels in attention-deficit/hyperactivity disorder patients. Future studies should clarify whether long-term methylphenidate treatment disrupts testosterone production as well as the function of the reproductive system. [ABSTRACT FROM AUTHOR]

Background: Studies have shown the involvement of cannabinoid (CB) receptors in the behavioral and neurobiological effects of psychostimulants. Most of these studies have focused on the role of CB1 receptors in the psychostimulant effects of cocaine, while very few have investigated the respective role of CB2 receptors. Further studies are warranted to elucidate the extent of CB receptor involvement in the expression of cocaine-induced effects. Methods: The role of CB1 and CB2 receptors in the rewarding and motor properties of cocaine was assessed in conditioned place preference, conditioned motor activity, and open field activity in rats. Results: The CB1 receptor antagonist rimonabant (3 mg/kg) decreased the acquisition and the expression of conditioned place preference induced by cocaine (20 mg/kg). Rimonabant inhibited cocaine-elicited conditioned motor activity when administered during the expression of cocaine-induced conditioned place preference. Rimonabant decreased ambulatory and vertical activity induced by cocaine. The CB2 receptor agonist JWH-133 (10 mg/kg) decreased the acquisition and the expression of cocaineinduced conditioned place preference. JWH-133 inhibited cocaine-elicited conditioned motor activity when administered during the acquisition and the expression of cocaine-induced conditioned place preference. JWH-133 decreased ambulatory activity and abolished vertical activity induced by cocaine. The effects of JWH-133 on cocaine conditioned and stimulated responses were abolished when the CB2 receptor antagonist/inverse agonist AM630 (5 mg/kg) was preadministered. Conclusions: Cannabinoid CB1 and CB2 receptors modulate cocaine-induced rewarding behavior and appear to have opposite roles in the regulation of cocaine's reinforcing and psychomotor effects. [ABSTRACT FROM AUTHOR]

Background. Parkinson disease (PD) impairs control of well-learned movements. Movement control improvements are found when individuals complete tasks while focusing attention externally on manipulating an object, which is argued to occur due to automatic processing associated with well-learned movements. Focusing attention internally (on movements of one's limbs) is believed to involve conscious control networks and hinders movement performance. Previous work has shown that an external focus of attention (EFA) improved postural stability in individuals with PD (compared with an internal focus of attention [IFA]), but this improvement occurred when patients were taking dopamine medication, which modulates basal ganglia functioning responsible for well-learned movements. Objective. The purpose of this study was to determine whether an EFA or IFA is beneficial for postural stability in individuals with PD in the absence of dopamine replacement. Design. A within-participant design was utilized. Methods. Nineteen individuals with PD stood on a firm, unstable platform in 3 attentional conditions: (1) EFA, (2) IFA, and (3) control (participant asked to stand still). Displacement and variability of anterior-posterior and medial-lateral postural sway were measured with a balance system for fall risk assessment. The protocol was completed both "on" and "off" (mininum 12-hour withdrawal of) dopaminergic medications. Results. While off medications, anterior-posterior sway variability was significantly lower during an IFA compared with the EFA and control. Anterior-posterior sway displacement and variability were significantly lower during the IFA, when off medications were compared with IFA and EFA while on medications. Limitations. There was no comparison with a healthy age-matched control group, and a safety harness was used due to task difficulty. Conclusions. An EFA may recruit automatic processes that involve degenerated basal ganglia in PD, and absence of dopamine exacerbates dysfunction. Training with an EFA may improve upon these automatic processes in individuals with PD. [ABSTRACT FROM AUTHOR]

Why do we make hasty decisions for short-term gain? Rapid decision-making with limited accumulation of evidence and delay discounting are forms of decisional impulsivity. The subthalamic nucleus is implicated in inhibitory function but its role in decisional impulsivity is less well-understood. Here we assess decisional impulsivity in subjects with obsessive compulsive disorder who have undergone deep brain stimulation of the limbic and associative subthalamic nucleus. We show that stimulation of the subthalamic nucleus is causally implicated in increasing decisional impulsivity with less accumulation of evidence during probabilistic uncertainty and in enhancing delay discounting. Subthalamic stimulation shifts evidence accumulation in subjects with obsessive-compulsive disorder towards a functional less cautious style closer to that of healthy controls emphasizing its adaptive nature. Thus, subjects with obsessive compulsive disorder on subthalamic stimulation may be less likely to check for evidence (e.g. checking that the stove is on) with no difference in subjective confidence (or doubt). In a separate study, we replicate in humans (154 healthy controls) using resting state functional connectivity, tracing studies conducted in non-human primates dissociating limbic, associative and motor frontal hyper-direct connectivity with anterior and posterior subregions of the subthalamic nucleus. We show lateralization of functional connectivity of bilateral ventral striatum to right anterior ventromedial subthalamic nucleus consistent with previous observations of lateralization of emotionally evoked activity to right ventral subthalamic nucleus. We use a multi-echo sequence with independent components analysis, which has been shown to have enhanced signal-to-noise ratio, thus optimizing visualization of small subcortical structures. These findings in healthy controls converge with the effective contacts in obsessive compulsive disorder patients localized within the anterior and ventral subthalamic nucleus. We further show that evidence accumulation is associated with anterior associative-limbic subthalamic nucleus and right dorsolateral prefrontal functional connectivity in healthy controls, a region implicated in decision-making under uncertainty. Together, our findings highlight specificity of the anterior associative-limbic subthalamic nucleus in decisional impulsivity. Given increasing interest in the potential for subthalamic stimulation in psychiatric disorders and the neuropsychiatric symptoms of Parkinson's disease, these findings have clinical implications for behavioural symptoms and cognitive effects as a function of localization of subthalamic stimulation. [ABSTRACT FROM AUTHOR]

Objective. The most prominent sensory sign of the complex regional pain syndrome (CRPS) is blunt hyperalgesia, but longitudinal studies on its relation to the outcome of long-termmultimodal treatment are lacking. Methods. We examined 24 patients with CRPS type I using standardized Quantitative Sensory Testing on the affected hand and the contralateral hand at baseline and 6 months following treatment. Somatosensory evoked potentials after single and paired-pulse stimulation of the median nerve were performed to assess the paired-pulse suppression (n519). Treatment response at follow-up was defined as pain relief >30% and improved hand function. Statistics: Wilcoxon test, Pearson correlation. Results. At baseline, similar to previous studies, the pressure pain threshold (PPT) was significantly decreased and the pain response to repeated pinprick stimuli was significantly increased, while all detection thresholds were within the normal range without any difference between the later treatment responders and non-responders. After 6 months of treatment, the PPT increased significantly in the whole study group. However, the pressure hyperalgesia improved only in treatment responders (n517, P< 0.05), whereas there was no improvement in nonresponders (n57). The rest of the sensory profile remained nearly unchanged. There was a correlation between the paired-pulse suppression and the PPT only at follow-up (r50.49, P< 0.05), but not at baseline, where low pressure pain threshold was associated with impaired paired-pulse suppression. Conclusion. Thus, the persistence of blunt hyperalgesia seems to be associated with impaired pairedpulse suppression, both representing maladaptive central nervous changes in CRPS, which may account for the treatment non-response in this subgroup. [ABSTRACT FROM AUTHOR]

Human herpesvirus 6B (HHV-6B) commonly reactivates after umbilical cord blood transplantation (UCBT) and is associated with delayed engraftment, fever, rash, and central nervous system dysfunction. Recently, CD134 (OX40) has been implicated as a potential viral entry receptor. We evaluated CD4+CD134+/neg-lo and CD8+CD134+/neg-lo cells at day 28 after UCBT in 20 subjects with previously documented HHV-6 reactivation and persistent viremia. Analysis of CD4+CD134+ cells as compared to CD4+CD134neg-lo cells showed 0.308 versus 0.129 copies of HHV-6B/cell (P = .0002). CD8+CD134+/neg-lo cells contained little to no HHV-6B copies. Following UCBT, CD4+CD134+ cells harbor significantly increased levels of HHV-6B, suggesting that CD134 (OX40) may facilitate viral entry. [ABSTRACT FROM AUTHOR]

Alzheimer’s disease (AD) is the most common cause of dementia. Its pathology often accompanies inflammatory action, and astrocytes play important roles in such procedure. Rela(p65) is one of significant message factors in NF-κB pathway which has been reported high expression in astrocyte treated by Aβ. HupA, an alkaloid isolated from Chinese herb Huperzia serrata, has been widely used to treat AD and observations reflected that it improves memory and cognitive capacity of AD patients. To reveal its molecular mechanisms on p65, we cultured astrocytes, built Aβ-induced AD model, treated astrocytes with HupA at different concentrations, assayed cell viability with MTT, and detected p65 expression by immunohistochemistry and PCR. Our results revealed that treatment with 10 μM Aβ1–42 for 24 h induced a significant increase of NF-κB in astrocytes; HupA significantly down-regulated p65 expression induced by Aβ in astrocytes. This study infers that HupA can regulate NF-κB pathway to treat AD. Immunostaining shows HupA decreases the expression of p65 induced by Aβ. [ABSTRACT FROM PUBLISHER]

Objectives: Biofilm formation and bacterial adherence are important requirements for persistence, multidrug resistance and infection. The d-amino acids play a role as modulators of bacterial growth and persistence, though their ability to inhibit biofilms is much debated. In this study, we analysed the effects of 18 different d-amino acids on the pathogens Acinetobacter baumannii and Pseudomonas aeruginosa.Methods: In vitro assays were carried out to analyse the effect of d-amino acids on bacterial growth, biofilm formation/disassembly, capacity to attach to eukaryotic cells and cellular death. In addition, in vivo assays were performed in mice, using experimental models of sepsis and pneumonia.Results: Biofilm formation was inhibited in A. baumannii by d-His, d-Cys and d-Trp (35%-86%) at 2 mM and in P. aeruginosa by d-Cys, d-Trp and d-Tyr (10%-30%) at 4 mM. Attachment to the A549 human alveolar cells was reduced in A. baumannii by d-Cys, d-His, d-Met, d-Val and d-Ser, and in P. aeruginosa by d-Arg and d-Trp. Growth was inhibited in A. baumannii by d-Cys and d-Trp, and in P. aeruginosa by d-Trp. In virulence assays, incubation of alveolar cells infected with P. aeruginosa with d-Cys, d-Trp and d-Arg reduced cell death (56%-45%). However, no significant effect of d-amino acids was observed in vivo.Conclusions: Some d-amino acids can inhibit bacterial growth, biofilm formation and adherence to eukaryotic cells in A. baumannii and P. aeruginosa, and showed a protective effect against infection of alveolar cells with P. aeruginosa. Despite the fact that some considerable protection was observed in mice, survival differences between treated and control groups were not statistically significant. [ABSTRACT FROM AUTHOR]

Objectives: To evaluate the in vitro activity of anidulafungin combined with amphotericin B or voriconazole against Candida spp. biofilms.Methods: Four Candida albicans, four Candida tropicalis, four Candida glabrata, two Candida parapsilosis and two Candida orthopsilosis blood isolates were tested by the microdilution chequerboard method combined with the XTT metabolic assay. Biofilm MIC was defined as the lowest concentration producing 50% metabolic inhibition with respect to control (BMIC50). Concentrations in the combinations ranged from 1/8 × BMIC50 to 4 × BMIC50 found for each antifungal tested alone.Results: Anidulafungin plus amphotericin B acted synergistically against C. albicans and C. glabrata biofilms [fractional inhibitory concentration index (FICI): 0.082-0.387], but showed no interaction against C. tropicalis, C. parapsilosis and C. orthopsilosis (FICI: 0.516-2.099). The combination of these antifungals failed to completely remove biofilms of C. albicans and C. glabrata, decreasing the metabolic activity of the biofilms up to 80% and 95%, respectively, which did not occur when each antifungal was used alone. Anidulafungin plus voriconazole showed no interaction against all isolates. Using a less stringent criterion previously proposed to define synergism (FICI < 1) and antagonism (FICI > 1.25), antagonistic interactions were found against some isolates.Conclusions: Anidulafungin with amphotericin B results in a synergistic effect against C. albicans and C. glabrata biofilms at serum concentrations of the drugs, but showed no interaction against C. tropicalis and C. parapsilosis complex. Anidulafungin plus voriconazole showed no interaction against the five Candida species assayed. Biofilms of C. tropicalis were found to be the most resistant towards the combinations assayed. The results presented may be of potential interest in the clinical setting. [ABSTRACT FROM AUTHOR]

Objectives: To evaluate the contribution of cysK and cysM to the fluoroquinolone (ofloxacin) antibiotic resistance in Salmonella Typhimurium, and their impact on H2S and cysteine production through targeted mutagenesis.Methods: Salmonella Typhimurium 14028s and its cysK and cysM mutants were tested for their susceptibility to ofloxacin, as determined by a broth microdilution test (to determine the MIC) and survival curves. H2S levels were measured by the Pb(AC)2 method and cysteine levels were determined using 5,5-dithio-bis-2-nitrobenzoic acid. DNA damage induced by antibiotic treatment was determined by PFGE. Finally, expression of cysK and cysM genes under antibiotic treatment was determined by real-time reverse transcription PCR.Results: As determined by MIC, the ΔcysK strain was more resistant to ofloxacin, a reactive oxygen species (ROS)-producing fluoroquinolone, than the WT and ΔcysM strains, which correlates with survival curves. Moreover, the ΔcysK strain exhibited higher H2S levels and lower cysteine levels than the WT strain. Finally, the ΔcysK strain exhibited lower DNA damage upon challenge with ofloxacin than the WT and ΔcysM strains. These results are in accordance with lower expression of cysK under ofloxacin treatment in the WT strain.Conclusions: This work demonstrated that cysteine metabolism in Salmonella Typhimurium modulated H2S levels, conferring resistance to second-generation fluoroquinolones. [ABSTRACT FROM AUTHOR]

Immune senescence as well as disturbed CD8+ T cell differentiation are a hallmark of chronic HIV infection. Here, we investigated to what extent immune senescence is reversible after initiation of anti-retroviral treatment (ART). Peripheral blood mononuclear cells (PBMCs) from a cohort of HIV patients with different disease courses, including untreated viral controllers ( n = 10), viral non-controllers ( n = 16) and patients on ART ( n = 20), were analysed and compared to uninfected controls ( n = 25) by flow cytometry on bulk and HIV-specific major histocompatibility complex (MHC) class I tetramer+ CD8+ T cells for expression of the memory markers CCR7 and CD45RO, as well as the senescence marker CD57 and the differentiation and survival marker CD127. Furthermore, a subset of patients was analysed longitudinally before and after initiation of ART. Frequencies of CD57+CD8+ T cells decreased after initiation of ART in central memory (Tcm) but not in effector memory T cell populations (TemRO and TemRA). The frequency of CD127+CD8+ cells increased in Tcm and TemRO. We observed a reduction of CD127- T cells in Tcm, TemRO and partially in TemRA subsets after initiation of ART. Importantly, HIV-specific CD8+ TemRO cells predominantly displayed a CD127-CD57+ phenotype in untreated HIV-patients, whereas the CD127+CD57- phenotype was under-represented in these patients. The frequency of the CD127+CD57-CD8+ T cell subpopulation correlated strongly with absolute CD4+ counts in HIV-infected patients before and after initiation of ART. These findings can be interpreted as a phenotypical correlate of CD8+ memory T cell differentiation and the premature 'ageing' of the immune system, which was even observed in successfully virally suppressed HIV patients. [ABSTRACT FROM AUTHOR]