Identification of an H antigen-like blood group antigen in sera of cancer patients using a novel monoclonal antibody raised against endometrial carcinoma.
An IgM class monoclonal antibody (MAb) was derived by immunizing BALB/c mice with a human endometrial carcinoma cell line. This MAb, termed C12, exhibited strong reactivity against endometrial carcinoma, but lesser reactivity against normal endometria. The antigen recognized by MAb C12 (C12 antigen) was detected by radiometric assay in sera from patients with various carcinomas, but not in sera from patients without carcinomas or in sera from normal individuals. MAb C12 was found to agglutinate blood type O erythrocytes, but not A, B, or AB erythrocytes. To clarify the specificity of MAb C12, tissue staining experiments were performed in parallel using MAb C12, Ulex europaeus lectin I (anti-H), and a monoclonal anti-H antibody. In endometrial carcinoma tissues, both H and C12 antigens increased, but the C12 antigen showed a prominent increase, in contrast to the H antigen. Further, the C12 antigen was not found in endothelial cells of blood type O patients. In sera, the level of the H antigen varied according to the host's blood type. The sera from blood type O individuals possessed higher levels of the H antigen than those with blood type A or B. Thus, the H antigen showed no value as a tumor-associated serum marker. In contrast, the presence of the C12 antigen in sera was not determined by ABO blood group status. Thus, MAb C12 was demonstrated to be a unique MAb that reacts with an H-like antigen occurring in the sera of patients with carcinomas irrespective of ABO blood group status. MAb C12 may prove to be a useful marker for cancer patient serum.


[Differential diagnosis of posterior cranial fossa: potentialities and unsolved problems].
Brain CT was made in 720 patients with tumors of the central nervous system. The subtentorial site of the process was encountered in 50.4% of cases. The paper outlines the skialogic characteristics of tumors having varying structures: medulloblastomas, ependymomas, astrocytomas, angioreticulomas, truncal gliomas, metastases, epidermoids, neurinomas, meningiomas, chemodectomas, arteriovenous malformations. Difficulties in determining the histostructure of tumors on the basis of skialogic manifestations were noted. Anatomic and skialogic approaches which may assume the type of neoplasmic process were outlined.


Beta-adrenergic-mediated extrarenal potassium disposal in patients with end-stage renal disease: effect of propranolol.
This study was designed to investigate beta-adrenergic-mediated extrarenal potassium disposal in patients with end-stage renal disease (ESRD). Plasma potassium was measured over a period of 3 months in 20 patients with ESRD who were receiving the nonselective beta-blocker propranolol (n = 10) or not (n = 10). Both groups were virtually anuric and had a comparable plasma BUN, plasma bicarbonate, and red cell Na-K-ATPase activity. Plasma potassium measured before dialysis was higher in propranolol users than in nonusers (5.6 +/- 0.2 and 4.6 +/- 0.1 mEq/l, p less than 0.005). To examine beta-adrenergic-mediated internal potassium disposal more directly, epinephrine and epinephrine plus propranolol were acutely administered to another group of patients with ESRD and to normal subjects. Epinephrine resulted in a similar fall in plasma potassium in both groups (0.69 +/- 0.20 and 0.63 +/- 0.07 mEq/l, respectively), thereby suggesting unimpaired beta-adrenergic-mediated extrarenal potassium handling in patients with ESRD. In patients, however, the response to epinephrine was heterogeneous. In 4 of the 10 patients studied, epinephrine infusion did not result in a decrement in plasma potassium suggesting impaired beta-adrenergic responsiveness and thus blunting of this mechanism of extrarenal potassium disposal. In the remaining 6 patients, epinephrine infusion resulted in a fall in plasma potassium which was greater than that observed in normal subjects (1.13 +/- 0.14 and 0.63 +/- 0.07 mEq/l, respectively, p less than 0.01). In the presence of propranolol, the infusion of epinephrine did not result in a decrement in plasma potassium in these 6 patients or in the 6 normal subjects (0.04 +/- 0.07 and -0.02 +/- 0.06 mEq/l, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)


Molecular impact of covalent modifications on nonribosomal peptide synthetase carrier protein communication.
Nonribosomal peptide synthesis involves the interplay between covalent protein modifications, conformational fluctuations, catalysis, and transient protein-protein interactions. Delineating the mechanisms involved in orchestrating these various processes will deepen our understanding of domain-domain communication in nonribosomal peptide synthetases (NRPSs) and lay the groundwork for the rational reengineering of NRPSs by swapping domains handling different substrates to generate novel natural products. Although many structural and biochemical studies of NRPSs exist, few studies have focused on the energetics and dynamics governing the interactions in these systems. Here, we present detailed binding studies of an adenylation domain and its partner carrier protein in apo-, holo-, and substrate-loaded forms. Results from fluorescence anisotropy, isothermal titration calorimetry, and NMR titrations indicated that covalent modifications to a carrier protein modulate domain communication, suggesting that chemical modifications to carrier proteins during NRPS synthesis may impart directionality to sequential NRPS domain interactions. Comparison of the structure and dynamics of an apo-aryl carrier protein with those of its modified forms revealed structural fluctuations induced by post-translational modifications and mediated by modulations of protein dynamics. The results provide a comprehensive molecular description of a carrier protein throughout its life cycle and demonstrate how a network of dynamic residues can propagate the molecular impact of chemical modifications throughout a protein and influence its affinity toward partner domains.


Results of laparoscopic cholecystectomy in a university hospital.
This study analyzed the first 100 laparoscopic cholecystectomies performed at a university teaching hospital by a single surgeon. Patients presented with chronic cholecystitis (92), acute cholecystitis (5), acalculus cholecystitis (2), and asymptomatic cholelithiasis (1). The operative time ranged from 59 minutes to 185 minutes (mean: 110 minutes). Cholangiography was performed in 88 patients, and common bile duct stones were discovered in 3. Choledocholithiasis was managed successfully through the cystic duct in all cases. Two procedures were converted to open cholecystectomy. Operative complications included ductal injury in one patient, bile leak in two, wound cellulitis in four, and atelectasis in one. Ninety-seven patients were released within 24 hours after surgery. Mean hospital charges for laparoscopic cholecystectomy were $828 less than the cost incurred for open cholecystectomy. These early results support the view that laparoscopic cholecystectomy is a safe, cost-effective method for performing cholecystectomy with a remarkable improvement in patient recovery time.


Monoamine oxidase A inhibition protects the myocardium after experimental acute volume overload.
The molecular pathway leading to myocardial cellular destruction after acute volume overload (AVO) may include monoamine oxidases. The aim of the present study was to investigate whether moclobemide (Mo), a monoamine oxidase inhibitor, protects the myocardium after AVO. Sixty syngeneic Fischer rats underwent surgical abdominal aortocaval fistula to induce AVO. Eighteen rats were treated with Mo 10 mg/kg/day and were compared with 42 untreated rats with AVO without treatment. Myocardial recovery was analyzed using quantitative reverse transcription polymerase chain reaction for hypoxia-inducible factor 1-alpha, inducible nitric oxide synthase, interleukin 6, E-selectin, atrial natriuretic peptide (ANP), brain natriuretic peptide, vascular endothelial growth factor-alpha, matrix metalloproteinase 9, chitinase 3-like protein (YKL-40), and transforming growth factor-beta. After 3 days, the relative number of ischemic intramyocardial arteries in the left ventricle was lower in AVO treated with Mo than in without [0.04 (0.02-0.07) vs. 0.09 (0.07-0.14), point score unit]. After 1 day, ANP was lower in AVO treated with Mo than in without [0.95 (0.37-1.84) vs. 2.40 (1.33-3.09), fold changes from the baseline (FC), p=0.044], whereas after 1 and 3 days, YKL-40 was higher in AVO treated with Mo than in without [22.66 (14.05-28.83) vs. 10.06 (6.23-15.02), FC, p=0.006 and 6.03 (4.72-7.18) vs. 3.70 (2.62-5.35), FC, p=0.025]. Mo decreases intramyocardial arterial ischemia of the left ventricle after AVO while increases YKL-40, reflecting cellular protection during early cardiac remodeling. In the future, adding Mo may be a simple means for myocardial protection after AVO.


[Monitoring of vital patient's functions by contact-free sensors].
An experimental device was constructed as well as hardware and software were designed to register the functional state parameters, i.e. external respiration functions, rhythmic heart activity and general motor activity (including the spastic and epileptic variations), when there is no direct galvanic contact with the patient's body.


Reduction in sample rejections at the preanalytical phase - Impact of training in a tertiary care oncology center.
Major clinical decisions are based on the laboratory test results where preanalytical errors are an important cause of repeat collections in patients. Identification of problem areas and continuous training of phlebotomy staff are important tools in reducing these errors. In this study, we looked at the most common causes of sample rejection in our setting and the efficacy of the corrective measures and training processes for staff in reducing preanalytical errors. This prospective study was conducted at the laboratory diagnostic services of a tertiary care oncology center, with a hematopoietic stem cell transplant unit during the period of 2012-2017 in two phases. Sample rejections from various wards were analyzed for types of rejections. In the first phase, we analyzed the problem areas (year 2012). Following a root cause analysis, current practices of training were altered. In the second phase (2013-2017), we studied the effects of these measures. The percent variation and P value for significance in sample rejections were calculated. During the year 2012, 0.36% samples were rejected by laboratory. Following interventions in the period from 2013 to 2017, samples rejected dropped to 0.19% (P < 0.0001), 0.09% (P < 0.0001), 0.09% (P = 0.8387), 0.05% (P = 0.0004), and 0.05% (P = 0.329), respectively. The reduction was significant from surgical oncology ward (P = 0.0107) and intensive care unit (P = 0.0007). From 2013 to 2017, errors significantly reduced to 0.015% for hemolyzed samples (P = 0.0001), 0.005% for contaminated samples, 0.036% for clotted samples, and 0.019% for labeling errors. Intervention in the form of targeted training helps reduce errors and improves the quality of results generated and contributes to better clinical outcomes.


Diagnosis and management of idiopathic pulmonary fibrosis: French practical guidelines.
Idiopathic pulmonary fibrosis (IPF) is the most frequent chronic idiopathic interstitial pneumonia in adults. The management of rare diseases in France has been organised by a national plan for rare diseases, which endorsed a network of expert centres for rare diseases throughout France. This article is an overview of the executive summary of the French guidelines for the management of IPF, an initiative that emanated from the French National Reference Centre and the Network of Regional Competence Centres for Rare Lung Diseases. This review aims at providing pulmonologists with a document that: 1) combines the current available evidence; 2) reviews practical modalities of diagnosis and management of IPF; and 3) is adapted to everyday medical practice. The French practical guidelines result from the combined efforts of a coordination committee, a writing committee and a multidisciplinary review panel, following recommendations from the Haute Autorité de Santé. All recommendations included in this article received at least 90% agreement by the reviewing panel. Herein, we summarise the main conclusions and practical recommendations of the French guidelines.


Comparative study of circadian clock models, in search of processes promoting oscillation.
We study simple models for circadian rhythm, and examine the condition in which the equilibrium is unstable, generating a sustained oscillation. In the models, a clock gene(s) is transcribed to produce mRNAs, which are translated to produce proteins that suppress the transcription of the clock gene(s). First, using a Lyapunov function, we prove under very general conditions that two-variable models cannot generate a stable oscillation, implying that additional structures are needed for the model to generate a sustainable rhythm. By comparing several models of different complexities using the Routh-Hurwitz criteria of stability, we show that a sustained oscillation is more likely to occur if the cell is compartmentalized and the proteins need to be transported from the cytosol to the nucleus, if the proteins have to be modified before entering the nucleus, if the kinetics of transcription inhibition or the transport to the nucleus have cooperativity with a nonlinear dependence on the substrate concentration, or if the products of two clock genes form a heterodimer that suppresses both of their own genes. We discuss the implications of these results.


Portable gas chromatograph with tunable retention and sensor array detection for determination of complex vapor mixtures.
A prototype portable gas chromatograph that combines a multiadsorbent preconcentrator/focuser, a tandem-column separation stage with individual column temperature control and junction point pressure modulation, and a detector consisting of an integrated array of polymer-coated surface acoustic wave microsensors is described. Using scheduled first-column stop-flow intervals and independent temperature programming of the two columns, it is possible to adjust the retention of eluting analyte vapors to maximize vapor recognition with the microsensor array and minimize the time of analysis. A retention window approach is combined with Monte Carlo simulations to guide retention tuning requirements and facilitate pattern recognition analyses. The determination of a 30-vapor mixture of common indoor air contaminants in < 10 min is demonstrated using ambient air as the carrier gas. Detection limits of < 10 ppb are achieved for the majority of compounds from a 1-L air sample on the basis of the most sensitive sensor in the array. Performance is assessed in the context of near-real-time indoor air quality monitoring applications.


Investigation of Cytomegalovirus in Intestinal Tissue in a Country With High CMV Seroprevalence.
In Turkey, cytomegalovirus (CMV) seropositivity has been reported to be high, between 85 and 100%. CMV has been responsible for disease exacerbation in inflammatory bowel disease (IBD). We aimed to evaluate the presence of CMV in intestinal tissue by immunohistochemical staining in IBD and non-IBD patient groups, in a country with high CMV seroprevalence. In this prospective cross-sectional study, the presence of intestinal CMV was investigated with tissue immunohistochemistry (IHC) staining, which is accepted as the gold standard method, and with polymerase chain reaction (PCR) in tissue and blood. Patients (≥18 years old, n = 189) who had a colonoscopic biopsy between January and May 2017 were included in the study at our hospital. Clinical, laboratory, endoscopic, and histopathological data of patients were assessed by dividing them into IBD (n = 34) and non-IBD (n = 155) groups. In this study, 567 colonic biopsy samples from 189 patients were evaluated. Tissue IHC staining was positive for 3 (1.58%) non-IBD patients. One of them was diagnosed as CMV ileitis. CMV DNA was also detected in 14 plasma (7.40%, <80-469 copies/mL) and 20 tissue samples (10.69%, 7-15 289 copies/mL). Tissue IHC staining is accepted as the gold standard for CMV ileitis, and the sensitivity and specificity of tissue PCR was 33% and 89.67%, while the sensitivity and specificity of plasma PCR was 66.66% and 93.54%, respectively. Although CMV seroprevalence is high in Turkey, CMV ileitis was diagnosed in only one non-IBD patient (0.53%). Compared to tissue IHC staining, the sensitivity of tissue and blood CMV PCR was low while their specificity was higher.


Ion channels on microglia: therapeutic targets for neuroprotection.
Under pathological conditions microglia (resident CNS immune cells) become activated, and produce reactive oxygen and nitrogen species and pro-inflammatory cytokines: molecules that can contribute to axon demyelination and neuron death. Because some microglia functions can exacerbate CNS disorders, including stroke, traumatic brain injury, progressive neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis, and several retinal diseases, controlling their activation might ameliorate immune-mediated CNS disorders. A growing body of evidence now points to ion channels on microglia as contributing to the above neuropathologies. For example, the ATP-gated P2X7 purinergic receptor cation channel is up-regulated around amyloid β-peptide plaques in transgenic mouse models of Alzheimer's disease and co-localizes to microglia and astrocytes. Upregulation of the P2X7 receptor subtype on microglia occurs also following spinal cord injury and after ischemia in the cerebral cortex of rats, while P2X7 receptor-like immunoreactivity is increased in activated microglial cells of multiple sclerosis and amyotrophic lateral sclerosis spinal cord. Utilizing neuron/microglia co-cultures as an in vitro model for neuroinflammation, P2X7 receptor activation on microglia appears necessary for microglial cell-mediated injury of neurons. A second example can be found in the chloride intracellular channel 1 (CLIC1), whose expression is related to macrophage activation, undergoes translocation from the cytosol to the plasma membrane (activation) of microglia exposed to amyloid β-peptide, and participates in amyloid β-peptide-induced neurotoxicity through the generation of reactive oxygen species. A final example is the small-conductance Ca2+/calmodulin-activated K+ channel KCNN4/KCa3.1/SK4/IK1, which is highly expressed in rat microglia. Lipopolysaccharide-activated microglia are capable of killing adjacent neurons in co-culture, and show markedly reduced toxicity when treated with an inhibitor of KCa3.1 channels. Moreover, blocking KCa3.1 channels mitigated the neurotoxicity of amyloid β-peptide-stimulated microglia. Excessive microglial cell activation and production of potentially neurotoxic molecules, mediated by ion channels, may thus constitute viable targets for the discovery and development of neurodegenerative disease therapeutics. This chapter will review recent data that reflect the prevailing approaches targeting neuroinflammation as a pathophysiological process contributing to the onset or progression of neurodegenerative diseases, with a focus on microglial ion channels and their neuroprotective potential.


Use of simulation-based learning among perioperative nurses and students: A scoping review.
Simulation-based learning has been extensively explored, especially in baccalaureate nursing programmes. Recently, simulation-based learning has been introduced in perioperative nursing. The aim of this scoping review is to investigate work published on the use of simulation-based learning in the field of perioperative nursing. A scoping review was conducted using the methodological framework of Arksey and O'Malley to identify a broad range of relevant literature, regardless of study design. A comprehensive and systematic search was performed using Medline, CINAHL, Eric, Svemed+, PsychINFO and Embase in May 2016 and then was updated in February 2018. Each database was searched for literature published between 1st January 2005 and 8th February 2018. Two authors independently assessed literature eligibility and extracted data to answer our research question 'What is known about the use of simulation-based learning in the field of perioperative nursing?' Nine articles and one doctoral thesis were included in the review. There appears to be a paucity of research or results-oriented evidence regarding the use of simulation-based learning in the field of perioperative nursing. Different goals of simulation-based learning were reported. It was difficult to confirm whether these goals had been reached as none of the articles included control groups, and no evaluations had been undertaken against Kirkpatrick's level 3 to see changes in participants' behaviours, and level 4, to determine whether the training had a positive impact on, for example, patient outcomes. Owing to the lack of research and the inadequate descriptions of design and method in simulation-based learning in most of the articles included, there is little evidence in the existing literature to guide practitioners of this learning in the field of perioperative nursing. This indicates a need for further research in this area.


Characterization of trade-offs between immunity and reproduction in the coral species Astrangia poculata.
Living organisms face ubiquitous pathogenic threats and have consequently evolved immune systems to protect against potential invaders. However, many components of the immune system are physiologically costly to maintain and engage, often drawing resources away from other organismal processes such as growth and reproduction. Evidence from a diversity of systems has demonstrated that organisms use complex resource allocation mechanisms to manage competing needs and optimize fitness. However, understanding of resource allocation patterns is limited across taxa. Cnidarians, which include ecologically important organisms like hard corals, have been historically understudied in the context of resource allocations. Improving understanding of resource allocation-associated trade-offs in cnidarians is critical for understanding future ecological dynamics in the face of rapid environmental change. Here, we characterize trade-offs between constitutive immunity and reproduction in the facultatively symbiotic coral Astrangia poculata. Male colonies underwent ex situ spawning and sperm density was quantified. We then examined the effects of variable symbiont density and energetic budget on physiological traits, including immune activity and reproductive investment. Furthermore, we tested for potential trade-offs between immune activity and reproductive investment. We found limited associations between energetic budget and immune metrics; melanin production was significantly positively associated with carbohydrate concentration. However, we failed to document any associations between immunity and reproductive output which would be indicative of trade-offs, possibly due to experimental limitations. Our results provide a preliminary framework for future studies investigating immune trade-offs in cnidarians.


Copper metal-organic polyhedra nanorods with high intrinsic peroxidase-like activity at physiological pH for bio-sensing.
Enzyme-mimicking nanomaterials (nanozymes) have been used to catalyze enzyme-like reactions for various applications. Despite these favorable properties, peroxidase-mimicking nanozymes suffer from the optimum reaction occurring in acidic solutions, which greatly limits their applications in biological systems. Herein, we demonstrate that copper Metal-Organic Polyhedra (Cu-MOP) nanorods exhibit high peroxidase-mimicking activity at a physiological pH value. Cu-MOP nanorods catalyze the generation of strong chemiluminescence signals in the presence of luminol/H2O2 and the oxidation of 2,2'-azinobis-(3-ethylbenzthiazoline-6-sulphonate acid) (ABTS) by H2O2 produces a green color reaction in a neutral pH solution. The Cu-MOP nanorod driven generation of color reactions is applied to develop a H2O2 sensor, and furthermore is implemented to develop a glucose detection platform.


Social media captures demographic and regional physical activity.
We examined the use of data from social media for surveillance of physical activity prevalence in the USA. We obtained data from the social media site Twitter from April 2015 to March 2016. The data consisted of 1 382 284 geotagged physical activity tweets from 481 146 users (55.7% men and 44.3% women) in more than 2900 counties. We applied machine learning and statistical modelling to demonstrate sex and regional variations in preferred exercises, and assessed the association between reports of physical activity on Twitter and population-level inactivity prevalence from the US Centers for Disease Control and Prevention. The association between physical inactivity tweet patterns and physical activity prevalence varied by sex and region. Walking was the most popular physical activity for both men and women across all regions (15.94% (95% CI 15.85% to 16.02%) and 18.74% (95% CI 18.64% to 18.88%) of tweets, respectively). Men and women mentioned performing gym-based activities at approximately the same rates (4.68% (95% CI 4.63% to 4.72%) and 4.13% (95% CI 4.08% to 4.18%) of tweets, respectively). CrossFit was most popular among men (14.91% (95% CI 14.52% to 15.31%)) among gym-based tweets, whereas yoga was most popular among women (26.66% (95% CI 26.03% to 27.19%)). Men mentioned engaging in higher intensity activities than women. Overall, counties with higher physical activity tweets also had lower leisure-time physical inactivity prevalence for both sexes. The regional-specific and sex-specific activity patterns captured on Twitter may allow public health officials to identify changes in health behaviours at small geographical scales and to design interventions best suited for specific populations.


Hypoxia Stress Response Pathways: Modeling and Targeted Therapy.
Hypoxia is a consequence of the decrease in the oxygen reaching the tissues of the body. It is a prominent feature of most solid tumors and is known to promote malignant progression, metastatic capacity, resistance to chemotherapy, and leads to poor patient prognosis. When a cell is under hypoxic stress, a cascade of cell signals is initiated through a family of transcription factors named as hypoxia inducible factors (HIFs). During hypoxia, HIF stabilizes and enters the nucleus and binds to the DNA via the hypoxia response element (HRE) and leads to the translation of downstream genes. The decision of adaptation or cell death depends on the extent of hypoxic stress faced by the cells. Proper understanding of hypoxic stress response is critical for understanding the mechanism of tumor cell adaptation to hypoxia and to develop efficient therapeutic interventions. In this paper, we develop a Boolean network model with targeted drug intervention in a cell that mimics persistent hypoxia. This hypoxic pathway is combined with pathways that help the cell adapt to the situation or undergo cell death. It is linked to apoptosis, cell survival, and energy production via the p53/Mdm2, PI3k/Akt/mTOR, and Glycolysis/TCA cycle pathways, respectively. In this model, we have incorporated eight known anticancer drugs that target these pathways. Through simulations, we have identified drug combinations that provided overall benefits to the cell in comparison to the no intervention case. Where applicable, the behavior predicted by this model is in agreement with experimental observations from the published literature.


Why media representations of corporations matter for public health policy: a scoping review.
Media representations play a crucial role in informing public and policy opinions about the causes of, and solutions to, ill-health. This paper reviews studies analysing media coverage of non-communicable disease (NCD) debates, focusing on how the industries marketing commodities that increase NCD risk are represented. A scoping review identified 61 studies providing information on media representations of NCD risks, NCD policies and tobacco, alcohol, processed food and soft drinks industries. The data were narratively synthesized to describe the sample, media depictions of industries, and corporate and public health attempts to frame the media debates. The findings indicate that: (i) the limited research that has been undertaken is dominated by a focus on tobacco; (ii) comparative research across industries/risk-factors is particularly lacking; and (iii) coverage tends to be dominated by two contrasting frames and focuses either on individual responsibilities ('market justice' frames, often promoted by commercial stakeholders) or on the need for population-level interventions ('social justice' frames, frequently advanced by public health advocates). Establishing the underlying frameworks is crucial for the analysis of media representation of corporations, as they reflect the strategies that respective actors use to influence public health debates and decision making. The potential utility of media research lies in the insights that it can provide for public health policy advocates about successful framing of public health messages and strategies to counter frames that undermine public health goals. A better understanding of current media debates is of paramount importance to improving global health.


Prosthetic treatment of dentinogenesis imperfecta. A case report.
Prosthetic reconstruction was made on dentition affected by dentinogenesis imperfecta. The bite was first raised with fixed bite plates, and then with temporary acrylic bridges; finally full gold and veneer crowns were made in the posterior teeth. The crowns were retained on the severely attrited teeth with self-threading parapulpal screws (TMS, Whaledent International, New York, U.S.A.) and amalgam and composite resin (Consise, 3M Company, St Paul, U.S.A.) posts. The teeth seem to have enough strength to withstand the occlusal forces, and the dentine appears hard enough to retain parapulpal screws. The prosthetic construction is still functioning well today, 5 years after starting treatment.


Teacher-student relationships as compensatory resources for aggressive children.
This 2-year prospective investigation examined the association between the quality of teacher-student relationships and children's levels of aggression in a sample of 140 second- and third-grade aggressive children (M age = 8.18). Consistent with the proposed dual-risk compensatory hypothesis, positive teacher-student relationships were more beneficial for aggressive African American and Hispanic children than for aggressive Caucasian children. Data did not support a moderating effect of negative parent-child relationship quality on the association between supportive teacher-student relationships and aggression. Findings underscore the importance of recruiting and preparing teachers capable of establishing supportive relationships with aggressive African American and Hispanic children. Results also suggest the need for multiple reporters of relationship quality in future research.


Intensified antibiotic treatment of tuberculosis meningitis.
Meningitis is the most severe manifestation of tuberculosis, resulting in death or disability in over 50% of those affected, with even higher morbidity and mortality among patients with HIV or drug resistance. Antimicrobial treatment of Tuberculous meningitis (TBM) is similar to treatment of pulmonary tuberculosis, although some drugs show poor central nervous system penetration. Therefore, intensification of antibiotic treatment may improve TBM treatment outcomes. Areas covered: In this review, we address three main areas: available data for old and new anti-tuberculous agents; intensified treatment in specific patient groups like HIV co-infection, drug-resistance, and children; and optimal research strategies. Expert commentary: There is good evidence from preclinical, clinical, and modeling studies to support the use of high-dose rifampicin in TBM, likely to be at least 30 mg/kg. Higher dose isoniazid could be beneficial, especially in rapid acetylators. The role of other first and second line drugs is unclear, but observational data suggest that linezolid, which has good brain penetration, may be beneficial. We advocate the use of molecular pharmacological approaches, physiologically based pharmacokinetic modeling and pharmacokinetic-pharmacodynamic studies to define optimal regimens to be tested in clinical trials. Exciting data from recent studies hold promise for improved regimens and better clinical outcomes in future.


The Effect of Clozapine on Self-reported Duration of Sleep and Its Interaction With 23 Other Medications: A 5-Year Naturalistic Study.
Sedation is a common and incapacitating clozapine adverse effect, but the factors associated with sedation and its pharmacological management remain poorly studied. We conducted a retrospective cohort study based on deidentified electronic clinical records of clozapine-treated patients from the secondary mental health care provider for Cambridgeshire and Peterborough, United Kingdom. We first evaluated cross-sectionally the influence of clozapine dose, clozapine, and norclozapine plasma levels on self-reported hours slept, as a proxy for sedation, using bivariate correlation and then the longitudinal effect of changes in clozapine dose and other 23 medications using linear mixed effect models. We followed 241 clozapine-treated patients for 56 months on average, with 2237 face-to-face assessments in total. Patients slept for a mean of 9.35 h/d, with 46% reporting 10 h/d or more. Cross-sectionally, sleep duration did not correlate with clozapine dose (r = 0.14, P = 0.106), but with clozapine plasma levels (r = 0.38, P < 0.0001) and norclozapine plasma levels (r = 0.25, P = 0.005). Longitudinally, the final mixed-effects model revealed 4 pharmacological variables that had a significant impact on hours slept: clozapine, risperidone augmentation, and atenolol were associated with increased sleep, whereas aripiprazole augmentation was associated with decreased sleep. We found that 20 other psychotropic medications measured were not associated with changes in sleep when added to clozapine. Excess sleep is a clozapine level-dependent adverse effect. The impact of different augmentation strategies might help clinicians decide on the most adequate strategy, albeit further studies should confirm our results.


Plasma clearance of rat bikunin: evidence for receptor-mediated uptake.
Bikunin is a chondroitin sulphate-containing protease inhibitor with a molecular mass of 25 kDa. It is secreted into the blood by hepatocytes, and recent observations indicate that it may have an extravascular function. Here we have studied the plasma clearance of bikunin in rats and mice. On intravenous injection, radiolabelled bikunin was found to have a half-life of 10 min; in rats with ligated renal arteries, the clearance time was twice as long, implying that the kidneys account for half the uptake. As judged by gel filtration, the size of bikunin is similar to that of albumin. Autoradiographic analysis of kidneys removed 2 min after the injection of radiolabelled bikunin indicated that, despite its size, bikunin is cleared by glomerular filtration. On ligation of the renal arteries, the plasma concentration of bikunin increased linearly to at least four times normal. This finding shows that the non-renal uptake system is saturated and therefore presumably receptor-mediated. Most of the non-renal uptake of injected bikunin was found to occur in non-visceral tissues such as the skin. Analysis of skin samples by autoradiography after injection of radiolabelled bikunin suggested that bikunin had been transferred from the plasma to the interstitial space.


Studies on the metabolism of the neurotoxic tri-o-cresyl phosphate. Distribution, excretion, and metabolism in male cats after a single, dermal application.
The metabolism of a single, dermal dose of 50 mg/kg of [14C]tri-o-cresyl phosphate (TOCP) was studied in male cats. TOCP was applied to an unprotected, preclipped area on the back of the neck. Three animals were sacrificed on each of 0.5, 1, 2, 5, and 10 days following application. Radioactivity disappeared biexponentially from the dosing site with a faster initial rate; 73% of the dose disappeared in the first 12 h followed by a slower phase with a half-life of 2.03 days. No radioactivity was detected in the expired air. TOCP was absorbed from the skin and subsequently distributed throughout the body. Generally, the highest concentrations of radioactivity were associated with bile, gall bladder, urinary bladder, kidneys, and liver; the lowest were found in the neural tissues, muscle, and spleen. Within the 10-day experimental period, approximately 28% and 20% of the applied dose were recovered in the urine and feces, respectively. TOCP and its metabolites in the urine, feces, bile, and plasma were analyzed by high performance liquid chromatography and liquid scintillation counting. TOCP was the predominant compound in the feces (26.3% of total fecal radioactivity); it was detected in a smaller percentage in the urine (2.3% of total urinary radioactivity). The major metabolite in the urine was o-cresol followed by di-o-cresyl hydrogen phosphate and o-cresyl dihydrogen phosphate; in the feces di-o-cresyl hydrogen phosphate was the predominant metabolite followed by o-cresyl dihydrogen phosphate. Trace amounts of saligenin cyclic-o-tolyl phosphate, hydroxymethyl, and di(hydroxymethyl) TOCP were also detected in the urine and feces. Other metabolites identified in the urine and feces were the stepwise oxidation products of the methyl group of o-cresol. Unlike the feces, the bile contained mostly metabolites with only trace amounts of TOCP detected at 12 h and 24 h following application. o-Cresyl dihydrogen phosphate and di-o-cresyl hydrogen phosphate were the prevalent metabolites in the bile and plasma. While di(hydroxymethyl) TOCP was present in trace amounts in plasma, an appreciable amount of saligenin cyclic-o-tolyl phosphate, believed to be the active neurotoxic metabolite, was detected. This study shows that skin is an important port of entry for TOCP. Since TOCP represents organophosphorous chemicals capable of producing delayed neurotoxicity in test animals and in humans, it is essential that industrial hygiene control prevents skin contamination of workers handling these chemicals.


[Clinical significance of pointed medicamental and non-medicamental therapy in the staged combined treatment of radiculopathies].
We analysed the results of the treatment of 4205 patients with different forms of vertebrogenic radiculopathy. They suggest the efficacy of differential application of graduated medicamental therapy, reflexo- and physiotherapy depending on the period of clinical course of the disease.


One stage vertical rectus muscle recession using adjustable sutures under local anaesthesia.
To assess the results of visual axis alignment following one stage adjustable suture surgery to correct vertical diplopia. Eight patients with a mean age of 44.9 years (range 16-80 years) complaining of vertical diplopia underwent rectus muscle recession under local anaesthesia with intraoperative adjustment of sutures. Diplopia was secondary to superior oblique paresis in four patients, dysthyroid eye disease in two patients, superior rectus paresis in one patient, and one developed a consecutive deviation after previous squint surgery. The surgery consisted of seven single muscle recessions (six inferior recti and one superior rectus) and one two muscle recession (inferior and lateral recti). The surgery was performed under topical anaesthesia supplemented with a subconjunctival injection of local anaesthetic over the muscle insertions. The patients remained comfortable throughout their surgery. All had a reduction in their vertical deviation. Six were asymptomatic and were eventually discharged. One had residual diplopia which was well tolerated without further intervention. One had persistent troublesome diplopia which was corrected by temporary Fresnel prisms. He became asymptomatic after further surgery of a 1 mm inferior rectus advancement. One stage adjustable suture surgery is recommended in all cases of strabismus surgery when postoperative results would otherwise be unpredictable.


Agricultural Technology Adoption among Migrant Settlers and Indigenous Populations of the Northern Ecuadorian Amazon: Are Differences Narrowing?
We consider trends in the use of modern agricultural inputs of migrant settlers and indigenous populations in the Northern Ecuadorian Amazon and the demographic, socioeconomic, and land use-related factors affecting input use. It is widely believed that the different livelihood strategies and therefore different relationships to the land of indigenous populations and migrant settlers result in different uses of chemical inputs in agriculture. We analyze data from two panel surveys, one of migrant settler households and a separate panel of indigenous households. We find low input use among both types of households, particularly among two of the five main ethnicities of indigenous households in the study region, the Cofán and Waorani. Multivariate statistical models were run separately for each panel, with significant relationships found between several predictors and the use of pesticides and herbicides. Our results highlight continuing differences in land use patterns between households in the NEA.


Expression, Biochemistry, and Stabilization with Camel Antibodies of Membrane Proteins: Case Study of the Mouse 5-HT3 Receptor.
There is growing interest in the use of mammalian protein expression systems, and in the use of antibody-derived chaperones, for structural studies. Here, we describe protocols ranging from the production of recombinant membrane proteins in stable inducible cell lines to biophysical characterization of purified membrane proteins in complex with llama antibody domains. These protocols were used to solve the structure of the mouse 5-HT3 serotonin receptor but are of broad applicability for crystallization or cryo-electron microscopy projects.


Plasmon-driven methanol oxidation on PtAg nanoalloys prepared by improved pulsed laser deposition.
The methanol oxidation reaction (MOR) is crucial in many energy-conversion devices. Although intensive efforts have been devoted to improving the MOR catalytic activity of Pt-based catalysts by treatment or alloying, enhancing the MOR catalyst performance utilizing solar energy has been less investigated. PtAg nanoalloys, combining the intrinsic catalytic activity of Pt toward the MOR with the visible spectrum plasmonic response of Ag, are expected to be a good MOR catalyst for solar energy, however, it remains challenging to incorporate these immiscible elements into a nanoalloy in a controlled way using conventional synthetic techniques. Herein, we proposed a general strategy for alloying silver and platinum elements into single-phase solid-solution nanoparticles with arbitrarily desired composition by bonding pure Pt targets with pure Ag strips in an improved pulsed laser deposition. The as-prepared PtAg nanoalloys show two crystalline phases and an average particle size of about 4 nm. To prove utility, we use the PtAg nanoalloys as support-free MOR catalysts anchored on the surface of a glassy carbon electrode solidly and uniformly. The PtAg nanoalloys exhibit a mass catalytic activity of 3.6 A mg-1, which is 4.5 times higher than that of the commercial Pt/C catalyst. Besides, the PtAg nanoalloys exhibit a promising regenerability after reactivation by cyclic voltammetry. Furthermore, the MOR catalytic activity of PtAg nanoalloys increased by 16% under irradiation by simulated sunlight, which is attributed to the surface plasmon resonance as ascertained from the UV-vis absorption spectra and photocurrent response experiments. These studies are believed to provide a new strategy for the enhancement of MOR catalytic activity with visible light as the driving force.


Visualizing cortical response to optogenetic stimulation and sensory inputs using multispectral handheld optoacoustic imaging.
To date, the vast majority of intra-vital neuroimaging systems applied in clinic and diagnostics is stationary with a rigid scanning element, requires specialized facilities and costly infrastructure. Here, we describe a simple yet radical approach for optoacoustic (photoacoustic) brain imaging in vivo using a light-weight handheld probe. It enables multispectral video-rate visualization of hemoglobin gradient changes in the cortex of adult rats induced by whisker and forelimb sensory inputs, as well as by optogenetic stimulation of intra-cortical connections. With superb penetration and molecular specificity, described here in method holds major promises for future applications in research, routine ambulatory neuroimaging, and diagnostics.


[Analysis of polymorphism of CTG repetitive sequences in the gene of myotonic dystrophy in human populations of the Volga-Ural region].
Distribution of CTG repetitive sequences in the myotonic dystrophy (MD) gene was analyzed in ten populations of the Volga-Ural region, including Tatars, Chuvashes, Maris, Udmurts, Mordovians, Komis, and four ethnogeographical groups of Bashkirs. A total of 25 alleles were found (9 to 14 in individual populations), with each allele containing 5 to 34 trinucleotide repeats. The allele frequency distribution had two peaks corresponding to alleles with 5 and 11-14 CTG repeats. The frequency of the (CTG)5 allele varied from 0.23 to 0.47 in Maris and Mordovians, respectively. Regarding the (CTG)11-14 alleles, those containing 13 and 12 trinucleotides were most frequent in all populations; their frequencies varied from 0.15 in Mordovians to 0.24 in Maris and Bashkirs from the Abzelilovskii raion (district). Alleles with large numbers of repeats (more than 30) were only found in Tatars and Bashkirs from the Abzelilovskii raion, where their frequency was 0.01. The data obtained were compared with those on other human populations from various regions of the world. In general, the populations of the Volga-Ural region took an intermediate position between European and Asian populations (although were somewhat more similar to the latter ones) with respect to the distribution of allelic frequencies of the CTG repetitive sequences. In individual populations, the number of genotypes varied from 13 to 27 in Mordovians and Bashkirs from the Ilishevskii raion, respectively. The observed heterozygosity was the highest (91%) in Udmurts and the lowest (58%) in Mordovians; the average heterozygosity was 81%. Such a high heterozygosity, as well as the revealed differentiation of the populations with respect to the distribution of the allelic frequencies of CTG repetitive sequences in the MD gene, allow this polymorphic DNA locus to be considered a highly informative genetic marker of populations.


TGF-beta contributes to the shift toward Th2-type responses through direct and IL-10-mediated pathways in tumor-bearing mice.
In previous reports, we showed that tumor-derived TGF-beta induced overproduction of IL-10, and these suppressive cytokines caused macrophage suppression in EL4-bearing mice. Proliferation of T cells from EL-4, but not IL-2, whereas T cells from normal mice were responsive to IL-2. A balance between Th1- and Th2-type cytokine production in EL4-T in response to anti-CD3 Ab or phorbor myristate acetate plus A23187 shifted toward the Th2 dominant pattern. The prevention of TGF-beta and IL-10 activates in vivo by administration of anti-IL-10 Ab (anti-IL-10) or anti TGF-beta Ab (anti-TGF-beta) resulted in the reduction in EL4-T of both IL-4 dependent proliferation and Th2-dominant cytokine production induced by anti-CD-3 stimulation. In addition, the anti-TGF-beta treatment resulted in complete restoration in EL4-T of suppressed IL-2 responsiveness, IL-2R expression, and Th1-type cytokine production, whereas the anti-IL-10 treatment produced partial recovery. These results lead us to conclude that TGF-beta drives the shift in the Th1/Th2 balance toward Th2 via IL-10-mediated development of the Th2 responses and via inhibition of the Th1-type responses directly in EL4-bearing mice.


An Educational Network for Surgical Education Supported by Gamification Elements: Protocol for a Randomized Controlled Trial.
Traditionally, medical students have learned surgical skills by observing a resident physician or surgeon who is performing the technique. Due to inconsistent practice opportunities in the clinical setting, a disparity of skill levels among students has been observed. In addition, the poor availability of faculty professors is a limiting factor in teaching and adequately preparing medical students for their clerkship years. With the ongoing COVID-19 pandemic, medical students do not have access to traditional suturing learning opportunities. Didactic courses are available on videoconferencing platforms; however, these courses do not include technical training. Our overarching goal is to evaluate the efficacy and usability of web-based peer-learning for advanced suturing techniques (ie, running subcuticular sutures). We will use the Gamified Educational Network (GEN), a newly developed web-based learning tool. We will assess students' ability to identify and perform the correct technique. We will also assess the students' satisfaction with regard to GEN. We will conduct a prospective randomized controlled trial with blinding of expert examiners. First-year medical students in the Faculty of Medicine of Université de Montréal will be randomized into four groups: (1) control, (2) self-learning, (3) peer-learning, and (4) peer-learning with expert feedback. Each arm will have 15 participants who will learn how to perform running subcuticular sutures through videos on GEN. For our primary outcome, the students' ability to identify the correct technique will be evaluated before and after the intervention on GEN. The students will view eight videos and rate the surgical techniques using the Objective Structured Assessment of Technical Skills Global Rating Scale and the Subcuticular Suture Checklist as evaluation criteria. For our secondary outcomes, students will anonymously record themselves performing a running subcuticular suture and will be evaluated using the same scales. Then, a survey will be sent to assess the students' acceptance of the intervention. The study will be conducted in accordance with the Declaration of Helsinki and has been approved by our institutional review board (CERSES 20-068-D). No participants have been recruited yet. Peer learning through GEN has the potential to overcome significant limitations related to the COVID-19 pandemic and the lack of availability of faculty professors. Further, a decrease of the anxiety related to traditional suturing classes can be expected. We aim to create an innovative and sustainable method of teaching surgical skills to improve the efficiency and quality of surgical training in medical faculties. In the context of the COVID-19 pandemic, the need for such tools is imperative. ClinicalTrials.gov NCT04425499; https://clinicaltrials.gov/ct2/show/NCT04425499. PRR1-10.2196/21273.


CD4+ Th cells resembling regulatory T cells that inhibit chronic colitis differentiate in the absence of interactions between CD4 and class II MHC.
Regulatory CD4+ Th cells can prevent many autoimmune diseases; however, the factors selecting for these cells remain poorly defined. In transgenic mice with a mutation in the CD4 binding region on class II MHC, the disruption of CD4-class II interactions selected for CD4+ Th cells that expressed surface markers and cytokines associated with regulatory Th cells. Th cells from these mice were enriched for CD45RB(low) as well as CD25+, while they expressed high levels of the transcription factor associated with regulatory T cells, Foxp3, and cytokines, including IL-4, IL-10, and IFN-gamma mRNA and protein. These regulatory Th cells inhibited the function of APCs via IL-10 production, and adoptive transfer of these cells prevented weight loss and inflammation in a model of colitis. CD4+ regulatory Th cells emerged only when interactions between CD4 and class II MHC were deficient on cells of nonhemopoietic origin. These data support a novel model controlling the differentiation of regulatory Th cells and suggest that interactions between CD4 and class II MHC may a useful target for re-educating T cells as a treatment for inflammatory diseases.


Physiological Gait versus Gait in VR on Multidirectional Treadmill-Comparative Analysis.
Virtual reality (VR) is increasingly often finding applications in physiotherapy and health promotion. Recent years have seen the use of advanced technologies in the promotion of physical activity (PA) in society. New simulators, e.g., treadmills, enable the performance of PA (e.g., locomotive movements) in VR (artificially created virtual world). The question of how such movements are similar to natural forms of human locomotion (march, run) inspired the comparative analysis of physiological gait and gait in VR on a multidirectional Omni treadmill. The tests involved the use of the BTS Smart system for the triplanar analysis of motion. The test involved 10 healthy females aged 20-24 (weight: 52 ± 3.1 kg, height 162 ± 5.4 cm). Measurements were performed at two stages. The first stage involved the standard assessment of physiological gait, whereas the second was focused on gait forced by the Omni treadmill. The following gait parameters were analyzed: Flexion-extension in the ankle, knee joint and hip joint, rotation in the hip joint and knee joint, foot progression, adduction-abduction in the knee joint and hip joint, pelvic obliquity, pelvic tilt, pelvic rotation as well as energy expenditure and the movement of the body center of mass. The analysis of the test results revealed the existence of differences in the kinematics of physical gait and gait on the treadmill. The greatest differences were recorded in relation to the dorsal-plantar flexion in the ankle, the foot progression, the rotation of the knee joint, pelvic tilt and rotation. In addition, the gait on the treadmill is characterized by the longer duration of the stance phase and reduced ranges of the following movements: Flexion-extension in the ankle, knee joint and hip joint, adduction-abduction in the hip joint as well as rotation in the ankle and hip joint. The values of potential, kinetic and total energy recorded in relation to forced gait are significantly lower than those of physiological gait. Because of the fact that the parameters of gait on the Omni platform vary significantly from the parameters of physical gait, the application of the Omni treadmill in the re-education of gait during rehabilitation should be treated with considerable care. Nonetheless, the treadmill has adequate potential to become a safe simulator enabling active motion in VR using locomotive movements.


Comparing English-Language and Chinese-Language Assessment of DSM-5 Personality Disorders and Interpersonal Problems in Chinese Bilingual Speakers.
A review of the literature on Chinese translations of Western self-report personality disorder assessment measures indicates the need to empirically evaluate the validity of assessing Western personality disorder constructs in Chinese language and culture. The current study presents a novel approach to examining this critical question in cross-cultural clinical assessment science and practice. One hundred and ninety-nine (199) Mandarin Chinese and English bilingual participants (92 males and 107 females) provided both English and Chinese self-report ratings on the Inventory of Interpersonal Problems - Short Circumplex (IIP-SC) and The Personality Diagnostic Questionnaire - 4+ (PDQ-4+). The similarities and differences in associations between Diagnostic and Statistical Manual of Mental Disorders-5th edition (DSM-5) personality disorders and interpersonal problems assessed across languages were examined. The structural summary method (SSM) for circumplex data and a bootstrapping methodology were used to compute confidence intervals around SSM parameters to analyze and compare the interpersonal problems profiles for each personality disorder scale (e.g. narcissistic) derived from English-language and Chinese-language data. The current study found highly similar interpersonal profiles for personality disorder scales assessed in English and Chinese, suggesting Western DSM-5 personality disorder constructs generally emphasize the same interpersonal problems in Chinese language and culture. The method employed in this study also has implications for understanding whether translated measures capture the same personality constructs.


Grammatical Impairments in PPA.
Grammatical impairments are commonly observed in the agrammatic subtype of primary progressive aphasia (PPA-G), whereas grammatical processing is relatively preserved in logopenic (PPA-L) and semantic (PPA-S) subtypes. We review research on grammatical deficits in PPA and associated neural mechanisms, with discussion focused on production and comprehension of four aspects of morphosyntactic structure: grammatical morphology, functional categories, verbs and verb argument structure, and complex syntactic structures. We also address assessment of grammatical deficits in PPA, with emphasis on behavioral tests of grammatical processing. Finally, we address research examining the effects of treatment for progressive grammatical impairments. PPA-G is associated with grammatical deficits that are evident across linguistic domains in both production and comprehension. PPA-G is associated with damage to regions including the left inferior frontal gyrus (IFG) and dorsal white matter tracts, which have been linked to impaired comprehension and production of complex sentences. Detailing grammatical deficits in PPA is important for estimating the trajectory of language decline and associated neuropathology. We, therefore, highlight several new assessment tools for examining different aspects of morphosyntactic processing in PPA. Individuals with PPA-G present with agrammatic deficit patterns distinct from those associated with PPA-L and PPA-S, but similar to those seen in agrammatism resulting from stroke, and patterns of cortical atrophy and white matter changes associated with PPA-G have been identified. Methods for clinical evaluation of agrammatism, focusing on comprehension and production of grammatical morphology, functional categories, verbs and verb argument structure, and complex syntactic structures are recommended and tools for this are emerging in the literature. Further research is needed to investigate the real-time processes underlying grammatical impairments in PPA, as well as the structural and functional neural correlates of grammatical impairments across linguistic domains. Few studies have examined the effects of treatment for grammatical impairments in PPA; research in this area is needed to better understand how (or if) grammatical processing ability can be improved, the potential for spared neural tissue to be recruited to support this, and whether the neural connections within areas of dysfunctional tissue required for grammatical processing can be enhanced using cortical stimulation.


Effects of light intensity on circadian activity behaviour in the Indian weaverbird (Ploceus philippinus).
Circadian (locomotor activity/perching) behaviour of the weaverbird (Ploceus philippinus) under different light intensities was studied. Six groups of birds were subjected to 12L:12D (L = 1000 and 10 lux and D = 0.3 lux) for two weeks, and thereafter released into constant dim illumination (LL(dim) = 0.3 lux). After two weeks of LL(dim), birds were given a 2 h light pulse of 1000 lux at circadian time (CT) 12, 17 and 20, and exposure of LL(dim) was continued for another two weeks and the activity pattern was monitored. As expected, all birds were entrained under 12L:12D showing dense-activity in the group that was placed under light phase of 1000 lux. Under LL(dim) birds exhibited circadian activity rhythms with periods longer or shorter than 24 h. Light pulse at CT 12 caused small delay shift in the activity phase, but a larger delay in phase shift occurred when the pulse was given at CT 17. A pulse at CT 20 caused small advanced phase shift. Thus, photoperiodic weaverbird appears to show circadian system regulated behaviour as seen by activity-rest pattern under programmed light cycles.


Anti-hyperglycemic and anti-hyperlipidemic effects of a methanolic extract of Debregeasia salicifolia in Alloxan-induced diabetic albino mice.
Diabetes mellitus (DM), an endocrine syndrome characterized by high blood glucose levels due to abrogated insulin activity. The existing treatments for DM have side effects and varying degrees of efficacy. Therefore, it is paramount that novel approaches be developed to enhance the management of DM. Therapeutic plants have been accredited as having comparatively high efficacy with fewer adverse effects. The current study aims to elucidate the phytochemical profile, anti-hyperlipidemic, and anti-diabetic effects of methanolic extract D. salicifolia (leaves) in Alloxan-induced diabetic mice. Alloxan was injected intraperitoneally (150 mg kg-1, b.w), to induced diabetes in mice. The mice were divided into three groups (n=10). Group 1 (normal control) received normal food and purified water, Group II (diabetic control) received regular feed and clean water and group III (diabetic treated) received a methanolic extract of the plant (300 mg kg-1) for 28 days with a typical diet and clean water throughout the experiment. Blood samples were collected to checked serum glucose and concentration of LDL, TC, TG. The extract demonstrated significant antihyperglycemic activity (P<0.05), whereas improvements in mice's body weight and lipid profiles were observed after treatment with the extract. This study establishes that the extract has high efficacy with comparatively less toxicity that can be used for DM management.


Eptinezumab-jjmr, a humanized monoclonal specific to Calcitonin Gene Related Peptide, for the preventive treatment of migraine in adults.
Migraines are prevalent and cause significant morbidity, decline in quality of life and healthcare costs universally. Treatment options are varied, but efficacy is limited. This review centers on Eptinezumab-jjmr, a humanized monoclonal specific to CGRP for the prevention of migraines in adults. Herein presented are the science and mechanism of action, indication and clinical evidence for use. Migraines are severe, recurrent headaches, which are either episodic or chronic in nature. The pain is severe, often accompanied by co-morbid symptoms, such as photophobia, phonophobia, nausea and emesis, and is limiting in nature. It is a prevalent disorder that causes significant, worldwide disability, morbidity, suffering, and costs.The pathophysiology of migraines is actively studied, though recent research points to an initiating event causing migraine generation, that is then propagated by other brain regions, a significant one being the trigeminocervical complex. This is driven by biochemical transmitters, chiefly CGRP. This discovery led to the development of CGRP-targeting drugs, including gepants (small molecular antagonists) and anti-CGRP antibodies, such as Eptinezumab-jjmr.Traditional therapy includes preventative and abortive treatment; however, adherence with preventative treatment has been historically poor, and certain types of abortive therapy carry risks and side effects that preclude them from a large patient population. Moreover, traditional therapy often falls short in migraine therapy. CGRP antagonist, including Eptinezumab, aims to cover the gaps in migraine therapy. We present here evidence to support the safe and effective use of Eptinezumab for the prevention of migraines. Migraines are a prevalent primary headache disorder causing significant morbidity worldwide. Traditional abortive and preventative treatments fall short for many patients. Eptinezumab is part of new generation of CGRP-targeting medications and has shown significant evidence to support its use for the prevention of migraines. Further research is required to properly compare eptinezumab with existing pharmacotherapy and update guidelines on the appropriate combinations of therapies that are not available and the correct patient selection for each.


Comparative analysis of hazardous air pollutant emissions of casting materials measured in analytical pyrolysis and conventional metal pouring emission tests.
Demonstration-scale metal pouring emission tests and bench-scale Curie-point pyrolysis emission tests were conducted to identify and quantify the hazardous air pollutant (HAP) emissions of five kinds of casting materials, namely, bituminous coal, cellulose, conventional phenolic urethane binder (PUB), naphthalene-depleted PUB, and a collagen-based binder. For a given casting material, the major HAP species generated in Curie-point pyrolysis were essentially the same as those generated in demonstration-scale metal pouring. The 8-10 HAP species identified in the Curie-point pyrolysis tests comprised 65-98% (by weight) of the total HAP emissions quantified in the demonstration-scale pouring emission tests. Furthermore, with these two protocols, we appraised the relative emission changes that would be associated with (a) replacing conventional PUB with collagen-based binder, (b) replacing conventional PUB with naphthalene-depleted PUB, and (c) replacing bituminous coal with cellulose for making sand molds or cores in the casting process. The relative emission changes associated with the use of alternative casting materials exhibited similar trends for most of the major HAP species in the demonstration-scale pouring and Curie-point pyrolysis emission tests. The results indicated that Curie-point pyrolysis emission test could be employed as a convenient and cost-effective screening tool to identify the major HAP species and to compare the relative HAP emission levels for various casting materials.


Forced expression of the cell cycle inhibitor p57Kip2 in cardiomyocytes attenuates ischemia-reperfusion injury in the mouse heart.
Myocardial hypoxic-ischemic injury is the cause of significant morbidity and mortality worldwide. The cardiomyocyte response to hypoxic-ischemic injury is known to include changes in cell cycle regulators. The cyclin-dependent kinase inhibitor p57Kip2 is involved in cell cycle control, differentiation, stress signaling and apoptosis. In contrast to other cyclin-dependent kinase inhibitors, p57Kip2 expression diminishes during postnatal life and is reactivated in the adult heart under conditions of cardiac stress. Overexpression of p57Kip2 has been previously shown to prevent apoptotic cell death in vitro by inhibiting stress-activated kinases. Therefore, we hypothesized that p57Kip2 has a protective role in cardiomyocytes under hypoxic conditions. To investigate this hypothesis, we created a transgenic mouse (R26loxpTA-p57k/+) that expresses p57Kip2 specifically in cardiac tissue under the ventricular cardiomyocyte promoter Mlc2v. Transgenic mice with cardiac specific overexpression of p57Kip2 are viable, fertile and normally active and their hearts are morphologically indistinguishable from the control hearts and have similar heart weight/body weight ratio. The baseline functional parameters, including left ventricular systolic pressure (LVSP), left ventricular end diastolic pressure (LVEDP), LVdp/dtmax, heart rate (HR) and rate pressure product (RPR) were not significantly different between the different groups as assessed by the Langendorff perfused heart preparation. However, after subjecting the heart ex vivo to 30 minutes of ischemia-reperfusion injury, the p57Kip2 overexpressing hearts demonstrated preserved cardiac function compared to control mice with higher left ventricular developed pressure (63 +/- 15 vs 30 +/- 6 mmHg, p = 0.05), rate pressure product (22.8 +/- 4.86 vs 10.4 +/- 2.1 x 103bpm x mmHg, p < 0.05) and coronary flow (3.5 +/- 0.5 vs 2.38 +/- 0.24 ml/min, p <0.05). These data suggest that forced cardiac expression of p57Kip2 does not affect myocardial growth, differentiation and baseline function but attenuates injury from ischemia-reperfusion in the adult mouse heart.


Utility of serum CA19-9 levels in the diagnosis of pancreatic ductal adenocarcinoma in an endoscopic ultrasound referral population.
Recent data suggest the use of carbohydrate antigen (CA) 19-9 as a potential marker in the early detection of pancreatic ductal adenocarcinoma (PDAC) when used in the appropriate clinical setting. Here, we assess the utility of CA19-9 in PDAC detection in a select population of pancreatic endoscopic ultrasound (EUS) referrals. Retrospective review of an institutional EUS Pancreas Registry containing cases referred from November 2002 to November 2011 was completed for categorical analyses with CA19-9 level. A separate case-control study for the subset of non-elevated CA19-9 PDAC population was also performed to characterize the clinical features in this unique group of patients. Two hundred eighty-three patients had available CA19-9 data in the registry and were included in the study. Compared to the typical PDAC distribution, the proportion of patients with stage I disease was significantly higher in our registry population (P < 0.0001). Elevated CA19-9 levels most often reflected a diagnosis of PDAC relative to other pancreaticobiliary diagnoses. However, we observed that 15 % of patients with PDAC had normal CA19-9 levels. Clinical characteristics for this false-negative PDAC group compared to the true-positive group demonstrated a predilection for detection of cancer in the body/tail of the pancreas (P = 0.03), increased likelihood of lymph node metastases (P = 0.03), and initial presentation with vague abdominal pain or pancreatic mass as an incidental finding on imaging studies (P = 0.01). Elevated CA19-9 demonstrated a greater likelihood of PDAC diagnosis relative to benign pancreatic pathology, and higher levels of CA19-9 were in line with worse PDAC stage. Patients with normal CA19-9 PDAC may represent a unique subclass of patients, presenting with atypical clinical features, and possibly more advanced stage disease at the time of diagnosis. These patients may benefit from more diligent EUS examination or perhaps closer follow-up management.


Bleeding risk assessment in hemophilia A carriers from Dakar, Senegal.
: Hemophilia A carriers have an abnormal X chromosome with a molecular abnormality of FVIII gene. These carriers, long considered to be free of bleeding risk, could have the same symptoms as mild hemophiliacs. This study aim to assess bleeding risk of hemophilia A carriers monitored at the Clinical Hematology Department of Dakar. This is a prospective study of a period of 6 months including 22 hemophilia A carriers aged between 8 and 48 years. Hemophilia carriers were recruited using the genealogical tree of hemophiliacs followed in the service. Their diagnosis was carried out by long range PCR and Sanger sequencing method searching the molecular abnormality responsible for hemophilia in their family. Bleeding risk was determined using a questionnaire consisting of different bleeding symptoms quoted from -1 to 4 according to the severity. Total of different values allow to determine the bleeding score which was pathological if it was greater than or equal to 1. Medium age was 22.5 years (8-48) (SD = 9.28). Four hemophilia A carriers (18.1%) presented bleeding symptoms and had a bleeding score at least 1 (P = 0.02). Menorrhagia was predominant (13.6%) followed by epistaxis (9%), gingivorrhagia (9%), and prolonged bleeding after tooth extraction (9%). Factor VIII level was lower in hemophilia carriers who presented bleeding (42 ± 8.61 UI/l) versus hemophilia carriers without bleeding (100 ± 50.95 UI/l) (P = 0.001). There was no significant correlation between bleeding occurrence and age (P = 0.81), activated patial thromboplastin time value (P = 0.97) and FVIII/Von Willebrand Factor ratio (P = 0.12). One in five hemophilia carriers presented bleeding and the questionnaire was effective to identify hemophilia carriers who had a risk of bleeding.


Pathologic hip morphology in cerebral palsy and Down syndrome.
The pathogenesis and clinical course of hip dysplasia in cerebral palsy and Down syndrome is different than idiopathic developmental dysplasia of the hip. Unlike idiopathic developmental hip dysplasia, hip development in cerebral palsy and Down syndrome is typically normal in utero and instability develops after birth secondary to musculoskeletal disorders associated with the disease condition. For this reason, treatment protocols in Down syndrome and cerebral palsy hip dysplasia differ greatly from protocols designed to treat idiopathic hip dysplasia. The purpose of this review is to describe the pathologic hip morphology that results from cerebral palsy and Down syndrome.


The variegated aspects of Immunoglobulin A.
Although immunoglobulins (Ig) of the A isotype were discovered more than 50 years ago, their homeostatic function, production and specificity has only lately started to be unravelled. We have recently described that the level of IgAs is genetically determined and contributes to microbiota diversification via establishing a positive feedback loop of IgA production. Here we show that the amount of both fecal and serum IgAs is intermediate in a F1 BALB/c x C57BL/6 mixed background. Naïve mice that have never been exposed to certain bacterial strains but that carry innate IgAs that react towards those bacteria undergo de novo differentiation of antigen-specific responses, indicating that there is not just a recall of a pre-existing innate IgA response. We also demonstrate that, differently from pathogenic bacteria, a commensal does not induce systemic IgG response but only a mucosal IgA response. Thus IgAs come into different flavours and can potentiate their own production, but also drive the development of new specificities.


Disintegrating polymer multilayers to jump-start colloidal micromotors.
Colloidal systems with autonomous mobility are attractive alternatives to static particles for diverse applications. We present a complementary approach using pH-triggered disintegrating polymer multilayers for self-propulsion of swimmers. It is illustrated both experimentally and theoretically that homogenously coated swimmers exhibit higher velocity in comparison to their Janus-shaped counterparts. These swimmers show directional and random motion in microfluidic channels with a steep and shallow pH gradient, respectively. Further, a higher number of deposited polymer multilayers, steeper pH gradients and lower mass of the swimmers result in higher self-propulsion velocities. This new self-propulsion mechanism opens up unique opportunities to design, for instance, fast and yet biocompatible swimmers using the diverse tools of polymer chemistry to custom-synthesise the polymeric building blocks to assemble multilayers.


Reduced palatability in lithium- and activity-based, but not in amphetamine-based, taste aversion learning.
Conditioned taste aversions (CTA) based on lithium chloride (Experiment 1), amphetamine (Experiment 2), and wheel running (Experiment 3) were examined using the analysis of the microstructure of licking to measure the palatability of the taste serving as the conditioned stimulus (CS). Pairing saccharin with amphetamine reduced saccharin intake without reducing the size of licking clusters, initial lick rate, or the distribution of inter-lick intervals (ILIs) within a cluster. By contrast, pairing saccharin with lithium or wheel-running reduced saccharin intake as well as lick cluster size, initial lick rate, and the distribution of ILIs within a cluster. As lick cluster size, initial lick rate, and ILI distribution can be used as indices of stimulus palatability, the current results indicate that taste aversions based on either lithium or activity reduced the palatability of the CS. This suggests that aversions based on both lithium and wheel running involve conditioned nausea to the CS taste. The absence of similar changes in licking microstructure with amphetamine-based CTA is consistent with other evidence indicating this does not involve nausea.


De novo sequencing and initial annotation of the Mongolian gerbil (Meriones unguiculatus) genome.
The Mongolian gerbil (Meriones unguiculatus) is a member of the rodent family that displays several features not found in mice or rats, including sensory specializations and social patterns more similar to those in humans. These features have made gerbils a valuable animal for research studies of auditory and visual processing, brain development, learning and memory, and neurological disorders. Here, we report the whole gerbil annotated genome sequence, and identify important similarities and differences to the human and mouse genomes. We further analyze the chromosomal structure of eight genes with high relevance for controlling neural signaling and demonstrate a high degree of homology between these genes in mouse and gerbil. This homology increases the likelihood that individual genes can be rapidly identified in gerbil and used for genetic manipulations. The availability of the gerbil genome provides a foundation for advancing our knowledge towards understanding evolution, behavior and neural function in mammals. ACCESSION NUMBER: The Whole Genome Shotgun sequence data from this project has been deposited at DDBJ/ENA/GenBank under the accession NHTI00000000. The version described in this paper is version NHTI01000000. The fragment reads, and mate pair reads have been deposited in the Sequence Read Archive under BioSample accession SAMN06897401.


Escherichia coli with resistance factors in vegetarians, babies, and nonvegetarians.
The prevalence of Escherichia coli carrying resistance factors (R factors) was examined in meat-consuming individuals and in those not consuming meat (vegetarians and babies below the age of 6 months). Assuming that the transport of resistant E. coli from animals through meat and meat products to the human consumer is most important, with regard to the incidence of resistant E. coli in man, we expected a significant difference in the proportions of people with resistant E. coli between the two groups. However, the percentage with resistant E. coli was larger in the group of vegetarians and babies than in the group of meat-eating individuals.


[The modelling of a persistent parainfluenza infection].
A model of parainfluenza persistent infection was developed in guinea pigs, based on the use of the suckling-adapted virus and an immunosuppressor cyclophosphan. The latter increased the titre of virus and its antigen and duration of their detection in the organs, but the dynamics of these findings was different, and also delayed the time of appearance and slightly prolonged the period of detection of antibody.


Sol-Gel-Synthesis of Nanoscopic Complex Metal Fluorides.
The fluorolytic sol-gel synthesis for binary metal fluorides (AlF₃, CaF₂, MgF₂) has been extended to ternary and quaternary alkaline earth metal fluorides (CaAlF₅, Ca₂AlF₇, LiMgAlF₆). The formation and crystallization of nanoscopic ternary CaAlF₅ and Ca₂AlF₇ sols in ethanol were studied by 19F liquid and solid state NMR (nuclear magnetic resonance) spectroscopy, as well as transmission electron microscopy (TEM). The crystalline phases of the annealed CaAlF₅, Ca₂AlF₇, and LiMgAlF₆ xerogels between 500 and 700 °C could be determined by X-ray powder diffraction (XRD) and 19F solid state NMR spectroscopy. The thermal behavior of un-annealed nanoscopic ternary and quaternary metal fluoride xerogels was ascertained by thermal analysis (TG/DTA). The obtained crystalline phases of CaAlF₅ and Ca₂AlF₇ derived from non-aqueous sol-gel process were compared to crystalline phases from the literature. The corresponding nanoscopic complex metal fluoride could provide a new approach in ceramic and luminescence applications.


Safety and success of vaginal birth after cesarean delivery in patients with preeclampsia.
The objective of this study was to determine if preeclampsia (PRE) or gestational hypertension (GH) affects the rate of success of vaginal birth after cesarean delivery (VBAC), VBAC-related complications, or patient election to attempt VBAC. We performed a retrospective cohort study of all women who were offered VBAC from 1996 to 2000 in 17 community and university hospitals. Demographic, medical, and obstetric history, complications, treatment, and index pregnancy outcome information was collected on all patients in the database. Bivariate analysis and multivariable logistic regression were used to assess the independent association between GH and PRE and the rate of success of VBAC, VBAC-related complications, or patient election to attempt VBAC. A total of 25,005 patients were registered in the database. 13,706 (54.81%) attempted VBAC and 11,299 (45.19%) elected repeat cesarean delivery. After adjusting for confounding variables using multivariable logistic regression, patients with PRE were more likely to fail VBAC (relative risk [RR], 1.56; 95% CI, 1.22 to 2.00). Patients with GH were less likely to attempt VBAC (RR, 0.39; 95% CI, 0.34 to 0.46). A total of 304 (1.46%) patients had a uterine rupture. The VBAC group had a rupture rate of 0.93% and the elective cesarean group had a rupture rate of 0.04%. There was no difference in uterine rupture rates between the cohorts. Patients with gestational hypertension were less likely to attempt a VBAC. Patients with PRE, if they attempted a VBAC trial, had a higher VBAC failure rate. Patients with PRE or GH do not have increased uterine rupture rates. These findings can be used to improve mode of delivery counseling for VBAC candidate patients with preeclampsia.


Genomic analyses reveal global functional alterations that promote tumor growth and novel tumor suppressor genes in natural killer-cell malignancies.
Natural killer (NK)-cell malignancies are among the most aggressive lymphoid neoplasms with very poor prognosis. We performed array comparative genomic hybridization analysis on a number of NK cell lines and primary tumors to gain better understanding of the pathogenesis and tumor biology of these malignancies. We also obtained transcriptional profiles of genes residing in these regions and compared them with normal and activated NK cells. Only 30-50% of the genes residing in the gained or deleted regions showed corresponding increased or decreased expression. However, many of the upregulated genes in regions of gain are functionally important for the proliferation and growth of the neoplastic population. Genes downregulated in regions of loss included many transcription factors or repressors, tumor suppressors or negative regulators of the cell cycle. The minimal common region of deletion in 6q21 included three known genes (PRDM1, ATG5 and AIM1) showing generally low expression. Mutations resulting in truncated PRDM1 and changes in conserved amino-acid sequences of AIM1 were detected. Highly methylated CpG islands 5' of PRDM1 and AIM1 correlated with low expression of the transcripts. Reversal of methylation by Decitabine induced expression of PRDM1 and cell death. In conclusion, we have shown a general tumor-promoting effect of genetic alterations and have identified PRDM1 as the most likely target gene in del6q21. ATG5, an essential gene for autophagy and AIM1, a gene implicated in melanoma, may also participate in the functional abnormalities.


AMBN mutations causing hypoplastic amelogenesis imperfecta and Ambn knockout-NLS-lacZ knockin mice exhibiting failed amelogenesis and Ambn tissue-specificity.
Ameloblastin (AMBN) is a secreted matrix protein that is critical for the formation of dental enamel and is enamel-specific with respect to its essential functions. Biallelic AMBN defects cause non-syndromic autosomal recessive amelogenesis imperfecta. Homozygous Ambn mutant mice expressing an internally truncated AMBN protein deposit only a soft mineral crust on the surface of dentin. We characterized a family with hypoplastic amelogenesis imperfecta caused by AMBN compound heterozygous mutations (c.1061T>C; p.Leu354Pro/ c.1340C>T; p.Pro447Leu). We generated and characterized Ambn knockout/NLS-lacZ (AmbnlacZ/lacZ ) knockin mice. No AMBN protein was detected using immunohistochemistry in null mice. ß-galactosidase activity was specific for ameloblasts in incisors and molars, and islands of cells along developing molar roots. AmbnlacZ/lacZ 7-week incisors and unerupted (D14) first molars showed extreme enamel surface roughness. No abnormalities were observed in dentin mineralization or in nondental tissues. Ameloblasts in the AmbnlacZ/lacZ mice were unable to initiate appositional growth and started to degenerate and deposit ectopic mineral. No layer of initial enamel ribbons formed in the AmbnlacZ/lacZ mice, but pockets of amelogenin accumulated on the dentin surface along the ameloblast distal membrane and within the enamel organ epithelia (EOE). NLS-lacZ signal was positive in the epididymis and nasal epithelium, but negative in ovary, oviduct, uterus, prostate, seminal vesicles, testis, submandibular salivary gland, kidney, liver, bladder, and bone, even after 15 hr of incubation with X-gal. Ameloblastin is critical for the initiation of enamel ribbon formation, and its absence results in pathological mineralization within the enamel organ epithelia.


Cortical Gray-White Matter Blurring and Cognitive Morbidity in Focal Cortical Dysplasia.
Focal cortical dysplasia (FCD) is a malformation of cortical development that is associated with high rates of cognitive morbidity. However, the degree to which specific irregularities of dysplastic tissue directly impact cognition remains unknown. This study investigates the relationship between blurring of the cortical gray and white matter boundary on magnetic resonance imaging (MRI) and global cognitive abilities in FCD. Gray-white blurring (GWB) is quantified by sampling the non-normalized T1 image intensity contrast above and below the gray and white matter interface along the cortical mantle. Spherical averaging is used to compare resulting GWB for patients with histopathologically verified FCD with matched controls. Whole-brain correlational analyses are used to investigate the relationship between blurring and general cognitive abilities, controlling for epilepsy duration. Results show that cognitive performance is reduced in patients with FCD relative to controls. Patients show increased GWB in bilateral temporal, parietal, and frontal regions. Furthermore, increased GWB in these regions is linearly related to decreased cognition and mediates group differences in cognitive performance. These findings demonstrate that GWB is a marker of reduced cognitive efficiency in FCD that can potentially be used to probe general and domain-specific cognitive functions in other neurological disorders.


In vivo nanosecond laser axotomy: cavitation dynamics and vesicle transport.
Nanosecond laser pulses (lambda = 355 nm) were used to cut mechanosensory neurons in Caenorhabditis elegans and motorneurons in Drosophila melanogaster larvae. A pulse energy range of 0.8-1.2 microJ and < 20 pulses in single shot mode were sufficient to generate axonal cuts. Viability post-surgery was >95% for C. elegans and 60% for Drosophila. Cavitation bubble dynamics generated due to laser-induced plasma formation were observed in vivo by time-resolved imaging in both organisms. Bubble oscillations were severely damped in vivo and cavitation dynamics were complete within 100 ns in C. elegans and 800 ns in Drosophila. We report the use of this system to study axonal transport for the first time and discuss advantages of nanosecond lasers compared to femtosecond sources for such procedures.


Realization of a 15-channel, hermetically-encased wireless subretinal prosthesis for the blind.
A miniaturized, hermetically-encased, wirelessly-operated retinal prosthesis has been developed for implantation and pre-clinical studies in Yucatan mini-pig animal models. The prosthesis conforms to the eye and drives a microfabricated polyimide stimulating electrode array with sputtered iridium oxide electrodes. This array is implanted in the subretinal space using a specially-designed ab externo surgical technique that affixes the bulk of the prosthesis to the surface of the sclera. The implanted device includes a hermetic titanium case containing a 15-channel stimulator chip and discrete power supply components. Feedthroughs from the case connect to secondary power- and data-receiving coils. In addition, long-term in vitro pulse testing was performed on the electrodes to ensure their stability for the long lifetime of the hermetic case. The final assembly was tested in vitro to verify wireless operation of the system in biological saline using a custom RF transmitter circuit and primary coils. Stimulation pulse strength, duration and frequency were programmed wirelessly using a custom graphical user interface. Operation of the retinal implant has been verified in vivo in one pig for more than three months by measuring stimulus artifacts on the eye surface using a contact lens electrode.


Risperidone-related improvement of irritability in children with autism is not associated with changes in serum of epidermal growth factor and interleukin-13.
Risperidone has been shown to improve serious behavioral problems in children with autism. Here we asked whether risperidone-associated improvement was related to changes in concentrations of inflammatory molecules in the serum of these subjects. Seven molecules were identified as worthy of further assessment by performing a pilot analysis of 31 inflammatory markers in 21 medication-free subjects with autism versus 15 healthy controls: epidermal growth factor (EGF), interferon-γ (IFN-γ), interleukin (IL)-13, IL-17, monocyte chemoattractant protein-1 (MCP-1), IL-1 and IL-1-receptor antagonist. Serum concentrations of these markers were then established in a different set of subjects that participated in a double-blind, clinical trial and an expanded group of healthy subjects. In the first analysis, samples obtained from subjects with autism at baseline visits were compared to visits after 8-week treatment with placebo (n=37) or risperidone (n=40). The cytokine concentrations remained stable over the 8-week period for both risperidone and placebo groups. In the second analysis, we explored further the differences between medication-free subjects with autism (n=77) and healthy controls (recruited independently; n=19). Serum levels of EGF were elevated in subjects with autism (median=103 pg/mL, n=75) in comparison to healthy controls (75 pg/mL, n=19; p<0.05), and levels of IL-13 were decreased in autism (median=0.8 pg/mL, n=77) in comparison to controls (9.8 pg/mL, n=19; p=0.0003). These changes did not correlate with standardized measures used for a diagnosis of autism. In summary, risperidone-induced clinical improvement in subjects with autism was not associated with changes in the serum inflammatory markers measured. Whether altered levels of EGF and IL-13 play a role in the pathogenesis or phenotype of autism requires further investigation.


Hematopoietic stem cell transplantation for Gaucher disease.
Gaucher disease is the most common lysosomal storage disorder caused by a deficiency of the enzyme glucocerebrosidase. Current treatment of the disease involves a choice among enzyme replacement therapy, substrate reduction therapy and stem cell transplantation. Stem cell transplantation is a high risk procedure with possible long-term benefits in the regression of skeletal and neurological changes in people with Gaucher disease. To determine the role of hematopoietic stem cell transplantation in people with Gaucher disease in relation to: mortality risk associated with the procedure; efficacy in modifying the course of the disease; and arrest or regression of neurological manifestations in neuropathic forms (Types 2 and 3). We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Inborn Errors of Metabolism Trials Register which comprises of references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings.Date of the most recent search of the Group's Haemoglobinopathies Trials Register: 26 March 2012.We also searched the websites www.clinicaltrials.gov and www.genzymeclinicalresearch.com. Date of most recent search of these sites: 16 February 2012. All randomised, quasi-randomised and controlled clinical trials comparing stem cell transplantation with enzyme replacement therapy, substrate reduction therapy, symptomatic treatment or no treatment in people with Gaucher disease of all ages. We independently assessed trials for inclusion, however, no relevant trials were identified. Twelve trials were identified by the searches, however, these were not suitable for inclusion in the review. Stem cell transplantation is a form of treatment that offers the potential of permanent cure. However, there are no clinical trials that have assessed the safety and efficacy of stem cell transplantation in comparison to other conservative measures (enzyme replacement therapy, substrate reduction therapy) now in use.


The interaction between the malaria parasite and the red cell membrane.
The malaria parasite intimately interacts with the host red cell membrane throughout the cycle of invasion and intracellular development. Direct interaction between the merozoite surface and the red cell membrane involves specific binding between the surface components of both cells, which leads to the subsequent endocytotic process still incompletely understood. Intracellular development of the parasite is accompanied by various changes in the structure and function of red cell membrane components. Some changes may benefit parasite survival while others trigger host immune response. An understanding of both the direct interaction between the surface components of the parasite and the red cell during invasion, and the subsequent changes in the red cell membrane following invasion, should lead to better ways of controlling malaria.


Effects of Exercise Therapy on Balance Capacity in Chronic Stroke: Systematic Review and Meta-Analysis.
The purpose of this systematic review and meta-analysis was to investigate the effects of exercise training on balance capacity in people in the chronic phase after stroke. Furthermore, we aimed to identify which training regimen was most effective. Electronic databases were searched for randomized controlled trials evaluating the effects of exercise therapy on balance capacity in the chronic phase after stroke. Studies were included if they were of moderate or high methodological quality (PEDro score ≥4). Data were pooled if a specific outcome measure was reported in at least 3 randomized controlled trials. A sensitivity analysis and consequent subgroup analyses were performed for the different types of experimental training (balance and/or weight-shifting training, gait training, multisensory training, high-intensity aerobic exercise training, and other training programs). Forty-three randomized controlled trials out of 369 unique hits were included. A meta-analysis could be conducted for the Berg Balance Scale (28 studies, n=985), Functional Reach Test (5 studies, n=153), Sensory Organization Test (4 studies, n=173), and mean postural sway velocity (3 studies, n=89). A significant overall difference in favor of the intervention group was found for the Berg Balance Scale (mean difference 2.22 points (+3.9%); 95% confidence interval [CI], 1.26-3.17; P<0.01; I(2)=52%), Functional Reach Test (mean difference=3.12 cm; 95% CI, 0.90-5.35; P<0.01; I(2)=74%), and Sensory Organization Test (mean difference=6.77 (+7%) points; 95% CI, 0.83-12.7; P=0.03; I(2)=0%). Subgroup analyses of the studies that included Berg Balance Scale outcomes demonstrated a significant improvement after balance and/or weight-shifting training of 3.75 points (+6.7%; 95% CI, 1.71-5.78; P<0.01; I(2)=52%) and after gait training of 2.26 points (+4.0%; 95% CI, 0.94-3.58; P<0.01; I(2)=21, whereas no significant effects were found for other training regimens. This systematic review and meta-analysis showed that balance capacities can be improved by well-targeted exercise therapy programs in the chronic phase after stroke. Specifically, balance and/or weight-shifting and gait training were identified as successful training regimens.


Vulvar basal cell carcinoma: an infrequently metastasizing neoplasm.
A case of metastasizing basal cell carcinoma (BCC) of the vulva is presented and compared with 10 nonmetastasizing tumors of the same histologic type by various clinicopathologic parameters. The former neoplasm manifested several features that distinguished it from most of the nonmetastasizing tumors, such as vaginal bleeding at presentation; advanced clinical stage; invasion of subcutaneous fat, urethra, and vagina; tumor thickness greater than 1 cm; and a morphealike pattern of growth. This series, in conjunction with previously published observations, would suggest that vulvar BCC behaves much like its counterpart in sites other than the vulva, locally recurring but metastasizing only on rare occasion. Simple wide excision of the tumor is curative in the majority of cases. More aggressive surgery may be warranted for large tumors that are locally destructive and extend into the subcutaneous fat, like our metastasizing case and the two other examples of metastasizing vulvar BCC in the literature. In this report, treatment options for vulvar BCC are discussed, as well as the use of the term "basosquamous" carcinoma, and whether vulvar BCC may be a manifestation of a more generalized syndrome of cutaneous basal cell neoplasia in some cases.