The efficacy of repaglinide monotherapy and in combination with metformin in Indonesian type 2 diabetes mellitus patients.
To investigate the efficacy and safety of repaglinide alone and in combination with metformin therapy. Seventy-two type 2 diabetes patients who were oral anti-diabetic drugs (OAD)-naive or currently on OAD for </=36 months with HbA1c </=9% and fasting plasma glucose (FPG) pound 13 mmol/L were recruited. Patients were titrated for 6 weeks to a dose level which maintained fasting blood glucose at 4.4-7.0 mmol/L and continued treatment for 8 weeks. Dose regimen started with 0.5 mg repaglinide each main meal, progressing to 1.0 mg repaglinide, 1.0 mg repaglinide + metformin 500 mg b.i.d. and 1.0 mg repaglinide + metformin 500 mg t.i.d., depending on patients' glycaemic status. Patients' glycaemic control (HbA(1c) and FPG), body weight and other safety parameters were evaluated. Thirty-seven patients completed the trial. Patients were overweight (mean BMI 25.5 +/- 4.1 kg/m(2)) with mean age 52.5 +/- 8.8 years and mean diabetes duration of 2.4 +/- 3.8 years. Mean HbA1c (2.26 +/- 0.22%, [p <0.05]) and FPG (3.31 +/- 0.47 mmol/L, [p <0.05]) decreased significantly from baseline. Body weight did not change significantly (0.85 +/-0.45 kg, p=0.068). Of the 33 patients who had baseline FPG >7.0 mmol/L, it appeared that repaglinide alone at doses 0.5 or 1.0 mg achieved FBG <7.0 mmol/L in 67% of patients. The majority of the treatment emergent adverse events were mild and unlikely related to trial product. Episodes of symptomatic hypoglycaemia were low (9.3%) in frequency. The changes in haematology, clinical biochemistry and urinalysis were mostly minor or remained unchanged. Vital signs and the results of physical examination also remained unchanged. Three of the four withdrawals were due to adverse events but were unlikely related to trial product. treatment with repaglinide alone and in combination with metformin was efficacious in glycaemic control in OAD-naive or previous users. Most of the patients appeared to achieve good control with repaglinide alone. The treatment regimens were safe (317 words).


The burden of influenza-associated critical illness hospitalizations.
Influenza is the most common vaccine-preventable disease in the United States; however, little is known about the burden of critical illness due to influenza virus infection. Our primary objective was to estimate the proportion of all critical illness hospitalizations that are attributable to seasonal influenza. Retrospective cohort study. Arizona, California, and Washington from January 2003 to March 2009. All adults hospitalized with critical illness, defined by International Classification of Diseases, 9th Edition, Clinical Modification diagnosis and procedure codes for acute respiratory failure, severe sepsis, or in-hospital death. We combined the complete hospitalization discharge databases for three U.S. states, regional influenza virus surveillance, and state census data. Using negative binomial regression models, we estimated the incidence rates of adult influenza-associated critical illness hospitalizations and compared them with all-cause event rates. We also compared modeled outcomes to International Classification of Diseases, 9th Edition, Clinical Modification-coded influenza hospitalizations to assess potential underrecognition of severe influenza disease. During the study period, we estimated that 26,760 influenza-associated critical illness hospitalizations (95% CI, 14,541, 47,464) occurred. The population-based incidence estimate for influenza-associated critical illness was 12.0 per 100,000 person-years (95% CI, 6.6, 21.6) or 1.3% of all critical illness hospitalizations (95% CI, 0.7%, 2.3%). During the influenza season, 3.4% of all critical illness hospitalizations (95% CI, 1.9%, 5.8%) were attributable to influenza. There were only 2,612 critical illness hospitalizations with International Classification of Diseases, 9th Edition, Clinical Modification-coded influenza diagnoses, suggesting influenza is either undiagnosed or undercoded in a substantial proportion of critical illness. Extrapolating our data to the 2010 U.S. population, we estimate that about 28,000 adults are hospitalized for influenza-associated critical illness annually. Influenza in many of these critically ill patients may be undiagnosed. Critical care physicians should have a high index of suspicion for influenza in the ICU, particularly when influenza is known to be circulating in their communities.


Relationships between biochemical and physiological changes induced by exercise in postmyocardial infarction patients.
AIM of the study was to examine the relationships between biochemical and physiological changes induced by exercise in postmyocardial infarction patients (PMIP) during the early stages of cardiac rehabilitation. Forty-nine male non-blockade recent PMIP, aged 63.8 ± 4.7 years, performed a graded exercise test on a motorised treadmill until volitional cessation or reaching any of the American College of Sports Medicine criteria. Blood pressure and rate-pressure product (RPP) were recorded every three minutes. A 12-lead electrocardiogram was monitored continuously and heart rate (HR) was taken from this. Blood samples were obtained by two methods; those used for testing blood lactate (BL) were taken from an already warmed finger tip before and during exercise, and the others used for enzymatic analysis based on lactate dehydrogenase (LDH), lactate dehydrogenase isoenzyme 1 (LDH-1), creatine kinase (CK) and creatine kinase polypeptide sub-unit MB (CK-MB) were collected by venipuncture from the antecubital vein pre and immediate post exercise test. Highly significant correlations existed between exercise-induced changes in HR, RPP, BL and ST segment level with increased enzymes activity in serum, and 73.1% to 90.1% of the variance in percentage increase of the enzyme activity could be predicted from the variance in percentage increase of HR during exercise. However, the mechanism of these relationships may differ. Since the rise in serum enzymes during submaximal exercise is primarily attributed to changes in membrane permeability in fatigued muscle, these relationships provide useful guidance to health professionals obtaining biochemical information about muscle fatigue.


Health concepts among socially disadvantaged children in France, Germany and Switzerland.
As health concepts develop through exposure to, and experience with particular contexts, and as health concepts influence health behaviour, it is important for actors in health promotion programmes to understand an individual's health concepts. This study focussed on health concepts among socially disadvantaged children in France, Germany, Italy and Switzerland-a hitherto less researched population group. We conducted focus groups with a total of 167 children aged 7-11 years (mean=8.76 years, SD=0.68). The aim of this study was to explore if the life situation across four different countries leads to similar health concepts, and how the particular, national health discourses are reflected in the children's health concepts. The data were analysed through a structured qualitative content analysis and revealed four categories: 'Symbols/symptoms of health/illness', 'Emotionality', 'Healthy/unhealthy practices', and 'Consequences of health problems'. The children's health concepts are linked to concrete events and objects, and they are able to think in logical sequences. However, the children's causal argumentation is uni-dimensional; they do not cover the complexity of the development of health problems. In particular, overweight stands for illness and is exclusively the result of unhealthy practices. In their concepts, the children reflect the national health promotion programme discourses about overweight. They seem to understand the messages of health education as 'behaving well means being healthy'; however, such a health education message initiates accusations of 'unhealthy persons'. In consequence, challenges for sensitive health education programmes (at school) are discussed.


Passive air sampling for semi-volatile organic chemicals.
During passive air sampling, the amount of a chemical taken up in a sorbent from the air without the help of a pump is quantified and converted into an air concentration. In an equilibrium sampler, this conversion requires a thermodynamic parameter, the equilibrium sorption coefficient between gas-phase and sorbent. In a kinetic sampler, a time-averaged air concentration is obtained using a sampling rate, which is a kinetic parameter. Design requirements for kinetic and equilibrium sampling conflict with each other. The volatility of semi-volatile organic compounds (SVOCs) varies over five orders of magnitude, which implies that passive air samplers are inevitably kinetic samplers for less volatile SVOCs and equilibrium samplers for more volatile SVOCs. Therefore, most currently used passive sampler designs for SVOCs are a compromise that requires the consideration of both a thermodynamic and a kinetic parameter. Their quantitative interpretation depends on assumptions that are rarely fulfilled, and on input parameters, that are often only known with high uncertainty. Kinetic passive air sampling for SVOCs is also challenging because their typically very low atmospheric concentrations necessitate relatively high sampling rates that can only be achieved without the use of diffusive barriers. This in turn renders sampling rates dependent on wind conditions and therefore highly variable. Despite the overall high uncertainty arising from these challenges, passive air samplers for SVOCs have valuable roles to play in recording (i) spatial concentration variability at scales ranging from a few centimeters to tens of thousands of kilometers, (ii) long-term trends, (iii) air contamination in remote and inaccessible locations and (iv) indoor inhalation exposure. Going forward, thermal desorption of sorbents may lower the detection limits for some SVOCs to an extent that the use of diffusive barriers in the kinetic sampling of SVOCs becomes feasible, which is a prerequisite to decreasing the uncertainty of sampling rates. If the thermally stable sorbent additionally has a high sorptive capacity, it may be possible to design true kinetic samplers for most SVOCs. In the meantime, the passive air sampling community would benefit from being more transparent by rigorously quantifying and explicitly reporting uncertainty.


Physical mapping of adenovirus type 2 temperature-sensitive mutations by restriction endonuclease analysis of interserotypic recombinants.
The genome structures of about 100 interserotypic ts recombinants produced in crosses between human adenovirus type 2 (H2) and 5 (H5) temperature-sensitive mutants were analyzed by cleavage with restriction endonucleases to determine the map coordinates of the following temperature-sensitive mutants: penton base plus fiber-defective H2 ts103, -104, and -136, assembly-defective H2 ts112, fiber-defective H2 ts125, hexon-defective H2 ts118 and -121, and DNA-negative H2 ts111. H5 ts1 (100 K defective), H5 ts36 (DNA negative), H5 ts125 (mutated in the early 72,000-dalton protein), H5 ts22 (fiber defective), H5 ts58 (IIIa defective), and H5 ts18 and -19 were used as one of the parents. The physical locations of the H2 temperature-sensitive mutations thus defined are discussed in relation to the genetic map, the biological function altered, and the positions of the structural genes on the genome.


A syllabus for Jewish medical ethics in the context of general bioethics.
Since the beginning of medical history, ethics has interested medical practitioners. The subject has become particularly important in recent years due to the huge advancements in medicine and medical technology and has elicited much public interest. While international ethical principles and guidelines have been established, classical Jewish tradition has always placed great emphasis on bioethics. Prof. Avraham Steinberg's monumental Encyclopedia of Jewish Medical Ethics presents the subject comprehensively and in depth. We propose a bioethics syllabus, to be integrated into the medical curriculum in three stages: i) preclinical - covering basic ethical concepts and principles, relevant history, and ethical codes; ii) clinical - covering bioethical topics relating to the human life cycle; iii) prior to students' final examinations and further specialization - covering bioethical topics relating to their personal interests. Steinberg's Encyclopedia is an ideal basis for the development of a professional course, including Jewish traditional aspects. Such a course would provide future physicians with a varied cultural and intercultural background, help shape their image, and improve the quality of medical care.


Optical node with time-space-and-wavelength domain contention resolution, deflection and dropping capability.
We experimentally demonstrate an optical node with time-space-and- wavelength domain contention resolution, deflection and dropping capability. The node is composed of an optical buffer based on an optical crossconnect and a wavelength converter. Although the experimental results are shown at 10 Gbit/s the bitrate can be increased substantially. Bit-error rate measurements are shown, sustaining only 3.5 dB power penalty after 10mus of optical buffering and agile wavelength conversion over 18nm span.


Effect of Vitamin B12 and Folic Acid Supplementation on Bone Mineral Density and Quantitative Ultrasound Parameters in Older People with an Elevated Plasma Homocysteine Level: B-PROOF, a Randomized Controlled Trial.
High plasma homocysteine (Hcy) levels are associated with increased osteoporotic fracture incidence. However, the mechanism remains unclear. We investigated the effect of Hcy-lowering vitamin B12 and folic acid treatment on bone mineral density (BMD) and calcaneal quantitative ultrasound (QUS) parameters. This randomized, double-blind, placebo-controlled trial included participants aged ≥65 years with plasma Hcy levels between 12 and 50 µmol/L. The intervention comprised 2-year supplementation with either a combination of 500 µg B12, 400 µg folic acid, and 600 IU vitamin D or placebo with 600 IU vitamin D only. In total, 1111 participants underwent repeated dual-energy X-ray assessment and 1165 participants underwent QUS. Femoral neck (FN) BMD, lumbar spine (LS) BMD, calcaneal broadband ultrasound attenuation (BUA), and calcaneal speed of sound (SOS) were assessed. After 2 years, FN-BMD and BUA had significantly decreased, while LS-BMD significantly increased (all p < 0.01) and SOS did not change in either treatment arm. No statistically significant differences between the intervention and placebo group were present for FN-BMD (p = 0.24), LS-BMD (p = 0.16), SOS (p = 0.67), and BUA (p = 0.96). However, exploratory subgroup analyses revealed a small positive effect of the intervention on BUA at follow-up among compliant persons >80 years (estimated marginal mean 64.4 dB/MHz for the intervention group and 61.0 dB/MHz for the placebo group, p = 0.04 for difference). In conclusion, this study showed no overall effect of treatment with vitamin B12 and folic acid on BMD or QUS parameters in elderly, mildly hyperhomocysteinemic persons, but suggests a small beneficial effect on BUA in persons >80 years who were compliant in taking the supplement.


Physicochemical interactions between rhamnolipids and Pseudomonas aeruginosa biofilm layers.
This study investigated the physicochemical interactions between a rhamnolipid biosurfactant and a biofilm layer. A concentration of 300 μg mL(-1) of rhamnolipids, which is around the critical micelle concentration value (240 μg mL(-1)), showed great potential for reducing biofilm. The surface free energy between the rhamnolipids and biofilm layer decreased, as did the negative surface charge, due to the removal of negatively charged humic-like, protein-like, and fulvic acid-like substances. The carbohydrate and protein concentrations composed of extracellular polymeric substances decreased by 31.6% and 79.6%, respectively, at a rhamnolipid concentration of 300 μg mL(-1). In particular, rhamnolipids can interact with proteins, leading to a reduction of the N source and amide groups on the membrane. For carbohydrates, the component ratio of glucosamine was decreased, but the levels of glucose and mannose that form the majority of the carbohydrates remained unchanged. To our knowledge, the present study is the first attempt at studying the interactions of the two phases of rhamnolipids and the biofilm layer, and as such is expected to clarify the mechanism by which rhamnolipids lead to a reduction in biofilm.


Characterization of ESBL/AmpC-producing extraintestinal Escherichia coli (ExPEC) in dogs treated at a veterinary hospital in Brazil.
The clinical aspects and lineages involved in Extraintestinal pathogenic Escherichia coli (ExPEC) infections in dogs remain largely unknown. In this study, we investigated the antimicrobial resistance and molecular structures of ExPECs isolated from infected dogs in Brazil. Samples were obtained from dogs (n = 42) with suspected extraintestinal bacterial infections. Phylogroup B2 was predominant (65.1%). No association was observed between the site of infection, phylogroups, or virulence factors. Almost half of the isolates (44.2%) were MDR, and 20.9% were extended-spectrum β-lactamase (ESBL)-positive. E. coli isolates that were resistant to fluoroquinolones (27.9%) were more likely to be MDR. The CTX-M-15 enzyme was predominant among the ESBL-producing strains, and seven sequence types were identified, including the high-risk clones ST44 and ST131. Single SNPs analysis confirmed the presence of two clonal transmissions. The present study showed a high frequency of ExPECs from phylogroup B2 infecting various sites and a high frequency of ESBL-producing strains that included STs frequently associated with human infection. This study also confirmed the nosocomial transmission of ESBL-producing E. coli, highlighting the need for further studies on the prevention and diagnosis of nosocomial infections in veterinary settings.


Giving Up on Consciousness as the Ghost in the Machine.
Consciousness as used here, refers to the private, subjective experience of being aware of our perceptions, thoughts, feelings, actions, memories (psychological contents) including the intimate experience of a unified self with the capacity to generate and control actions and psychological contents. This compelling, intuitive consciousness-centric account has, and continues to shape folk and scientific accounts of psychology and human behavior. Over the last 30 years, research from the cognitive neurosciences has challenged this intuitive social construct account when providing a neurocognitive architecture for a human psychology. Growing evidence suggests that the executive functions typically attributed to the experience of consciousness are carried out competently, backstage and outside subjective awareness by a myriad of fast, efficient non-conscious brain systems. While it remains unclear how and where the experience of consciousness is generated in the brain, we suggested that the traditional intuitive explanation that consciousness is causally efficacious is wrong-headed when providing a cognitive neuroscientific account of human psychology. Notwithstanding the compelling 1st-person experience (inside view) that convinces us that subjective awareness is the mental curator of our actions and thoughts, we argue that the best framework for building a scientific account is to be consistent with the biophysical causal dependency of prior neural processes. From a 3rd person perspective, (outside view), we propose that subjective awareness lacking causal influence, is (no more) than our experience of being aware, our awareness of our psychological content, knowing that we are aware, and the belief that that such experiences are evidence of an agentive capacity shared by others. While the human mind can be described as comprising both conscious and nonconscious aspects, both ultimately depend on neural process in the brain. In arguing for the counter-intuitive epiphenomenal perspective, we suggest that a scientific approach considers all mental aspects of mind including consciousness in terms of their underlying, preceding (causal) biological changes, in the realization that most brain processes are not accompanied by any discernible change in subjective awareness.


[Anti-arrhythmic effects of matrine].
Matrine (MT) is an alkaloid isolated from Sophra alopecuroids L. The LD50 of MT iv to mice was 72.1 mg/kg (95% CL 68.2-76.5 mg/kg). MT had significant effects on different experimental models of arrhythmias induced by aconitine, barium chloride or coronary ligation. The ECG of anesthetized rats was significantly changed after iv of MT. The HR was retarded and the PR and QTc intervals were prolonged.


Polymer Nanogels as Reservoirs To Inhibit Hydrophobic Drug Crystallization.
The effects of cross-link density and composition on the loading and in vitro dissolution of the drug phenytoin as amorphous solid dispersions in emulsion polymerized poly( N-isopropylacrylamide) (PNIPAm) and poly( N-isopropylacrylamide- co- N, N-dimethylacrylamide) nanogels were investigated near the lower critical solution temperature (LCST). Nanogel size and particle density in phosphate buffered saline were quantified by dynamic light scattering (DLS) and viscometry experiments, while drug-nanogel interactions were revealed by cross peaks in aqueous-state nuclear Overhauser effect spectroscopy measurements. Spray-dried dispersions (SDDs) of drug-loaded PNIPAm nanogel particles ( R ≈ 43 nm) were directly visualized by cryogenic transmission electron microscopy and further quantified by small-angle X-ray scattering during in vitro dissolution. SDD dissolution profiles were highly dependent on the nanogel cross-link density and directly correlated with the state of dispersion of the drug-loaded nanogel particles. A balance between net particle hydrophobicity and hydrophilicity along with the distance in temperature from the LCST are shown to dictate the in vitro dissolution of the amorphous solid dispersions. Solubility enhancement mechanisms disclosed in this study provide essential guidance for the design of effective nanogels for oral drug delivery applications.


Analysis of Extracellular Vesicles in the Tumor Microenvironment.
Extracellular vesicles (ECV) are membrane compartments shed from all types of cells in various physiological and pathological states. In recent years, ECV have gained an increasing interest from the scientific community for their role as an intercellular communicator that plays important roles in modifying the tumor microenvironment. Multiple techniques have been established to collect ECV from conditioned media of cell culture or physiological fluids. The gold standard methodology is differential centrifugation. Although alternative techniques exist to collect ECV, these techniques have not proven suitable as a substitution for the ultracentrifugation procedure.


Practice modulates motor-related beta oscillations differently in adolescents and adults.
Magnetoencephalography data were acquired during a leg force task in pre-/post-practice sessions in adolescents and adults. Strong peri-movement alpha and beta oscillations were mapped to the cortex. Following practice, performance improved and beta oscillations were altered. Beta oscillations decreased in the sensorimotor cortex in adolescents after practice, but increased in adults. No pre-/post-practice differences were detected for alpha oscillations. There is considerable evidence that there are motor performance and practice differences between adolescents and adults. Behavioural studies have suggested that these motor performance differences are simply due to experience. However, the neurophysiological nexus for these motor performance differences remains unknown. The present study investigates the short-term changes (e.g. fast motor learning) in the alpha and beta event-related desynchronizations (ERDs) associated with practising an ankle plantarflexion motor action. To this end, we utilized magnetoencephalography to identify changes in the alpha and beta ERDs in healthy adolescents (n = 21; age = 14 ± 2.1 years) and middle-aged adults (n = 22; age = 36.6 ± 5 years) after practising an isometric ankle plantarflexion target-matching task. After practice, all of the participants matched more targets and matched the targets faster, and had improved accuracy, faster reaction times and faster force production. However, the motor performance of the adults exceeded what was seen in the adolescents regardless of practice. In conjunction with the behavioural results, the strength of the beta ERDs across the motor planning and execution stages was reduced after practice in the sensorimotor cortices of the adolescents, but was stronger in the adults. No pre-/post-practice changes were found in the alpha ERDs. These outcomes suggest that there are age-dependent changes in the sensorimotor cortical oscillations after practising a motor task. We suspect that these noted differences might be related to familiarity with the motor task, GABA levels and/or maturational differences in the integrity of the white matter fibre tracts that comprise the respective cortical areas.


Circulating obestatin levels and the ghrelin/obestatin ratio in obese women.
We measured blood levels of obestatin, total ghrelin, and the ghrelin/obestatin ratio and their relationship with anthropometric and metabolic parameters, adiponectin and insulin resistance, in overweight/obese and normal-weight women. Outpatients Unit of Endocrinology of the S Orsola-Malpighi Hospital of Bologna, Italy. Fasting obestatin, ghrelin, adiponectin and lipid levels, fasting and glucose-stimulated oral glucose tolerance test insulin, and glucose levels were measured in 20 overweight/obese and 12 controls. The fasting ghrelin/obestatin ratio was calculated; the homeostasis model assessment-IR (HOMA-IR) and insulin sensitivity index (ISI(composite)) were calculated as indices of insulin resistance. Obese women had higher obestatin and lower ghrelin blood levels, and a lower ghrelin/obestatin ratio compared with controls. In all subjects, obestatin was significantly and positively correlated with total cholesterol and triglycerides, but not with ghrelin, anthropometric, and metabolic parameters. In the obese women, however, obestatin and ghrelin concentrations were positively correlated. By contrast, the ghrelin/obestatin ratio was significantly and negatively correlated with body mass index, waist, waist-to-hip ratio, fasting insulin, and HOMA-IR, and positively with ISI(composite) but not with adiponectin. None of these parameters were correlated with the ghrelin/obestatin ratio in the obese. Increased obestatin, decreased ghrelin levels, and a decreased ghrelin/obestatin ratio characterize obesity in women. This supports the hypothesis that the imbalance of ghrelin and obestatin may have a role in the pathophysiology of obesity. On the other hand, some relevant differences between our data on circulating levels of obestatin and the ghrelin/obestatin ratio in obese subjects and those reported in the few studies published so far imply that further research is needed.


Phylogeography of the Rock Shell Thais clavigera (Mollusca): Evidence for Long-Distance Dispersal in the Northwestern Pacific.
The present-day genetic structure of a species reflects both historical demography and patterns of contemporary gene flow among populations. To precisely understand how these factors shape current population structure of the northwestern (NW) Pacific marine gastropod, Thais clavigera, we determined the partial nucleotide sequences of the mitochondrial COI gene for 602 individuals sampled from 29 localities spanning almost the whole distribution of T. clavigera in the NW Pacific Ocean (~3,700 km). Results from population genetic and demographic analyses (AMOVA, ΦST-statistics, haplotype networks, Tajima's D, Fu's FS, mismatch distribution, and Bayesian skyline plots) revealed a lack of genealogical branches or geographical clusters, and a high level of genetic (haplotype) diversity within each of studied population. Nevertheless, low but significant genetic structuring was detected among some geographical populations separated by the Changjiang River, suggesting the presence of geographical barriers to larval dispersal around this region. Several lines of evidence including significant negative Tajima's D and Fu's FS statistics values, the unimodally shaped mismatch distribution, and Bayesian skyline plots suggest a population expansion at marine isotope stage 11 (MIS 11; 400 ka), the longest and warmest interglacial interval during the Pleistocene epoch. The lack of genetic structure among the great majority of the NW Pacific T. clavigera populations may be attributable to high gene flow by current-driven long-distance dispersal of prolonged planktonic larval phase of this species.


Association of systemic inflammation, adiposity, and metabolic dysregulation with asthma burden among Hispanic adults.
Obesity-related asthma is associated with higher disease burden than normal-weight asthma among Hispanics. Adiposity, metabolic dysregulation, and inflammation are all implicated in pathogenesis of obesity-related asthma, but their independent contributions are poorly understood. To examine the independent contributions of body fat distribution, metabolic abnormalities and inflammation on asthma symptoms and pulmonary function among Hispanics. Participants of the Hispanic Community Health Study/Study of Latinos with doctor-diagnosed asthma who completed an asthma symptom questionnaire and performed a valid spirometry were included in the analysis (n = 1126). Multivariate analysis was used to examine the independent association of general adiposity (assessed using body mass index), truncal adiposity (assessed by waist circumference), metabolic dysregulation (presence of insulin resistance and low HDL) and inflammation (high-sensitivity C-Reactive Protein≥3 mg/L) with reported asthma symptoms or pulmonary function measures (FEV1, and FVC) while adjusting for demographic and clinical covariates. Of the 1126 participants, 334 (29.5%) were overweight, and 648 (57.8%) were obese. FEV1 and FVC were lower in obese compared to normal-weight asthmatics. In analyses controlling for metabolic and adiposity factors, high hs-CRP (>7 mg/L) was associated with more symptoms (prevalence-ratio 1.27 (95%CI 1.05, 1.54), and lower FVC (β -138 ml (95%CI -27 ml, -249 ml)) and FEV1 (β -155 ml (95% CI -38 ml, -272 ml). Low HDL was also associated with lower FVC (β -111 ml (-22 ml, -201 ml) and FEV1 (β -100 ml (-12 ml, -188 ml)). Results were similar in men and women. Our findings suggest that hs-CRP and low HDL, rather than general and truncal adiposity, are associated with asthma burden among overweight and obese Hispanic adults.


Annexin A5 uptake in ischemic myocardium: demonstration of reversible phosphatidylserine externalization and feasibility of radionuclide imaging.
Ischemic insult to the myocardium is associated with cardiomyocyte apoptosis. Because apoptotic cell death is characterized by phosphatidylserine externalization on cell membrane and annexin-A5 (AA5) avidly binds to phosphatidylserine, we hypothesized that radiolabeled AA5 should be able to identify the regions of myocardial ischemia. Models of brief myocardial ischemia by the occlusion of the coronary artery for 10 min (I-10) and reperfusion for 180 min (R-180) for the detection of phosphatidylserine exteriorization using (99m)Tc-labeled AA5 and gamma-imaging were produced in rabbits. (99m)Tc-AA5 uptake after brief ischemia was compared with an I-40/R-180 infarct model. Histologic characterization of both myocardial necrosis and apoptosis was performed in ischemia and infarct models. Phosphatidylserine exteriorization was also studied in a mouse model, and the dynamics and kinetics of phosphatidylserine exposure were assessed using unlabeled recombinant AA5 and AA5 labeled with biotin, Oregon Green, or Alexa 568. Appropriate controls were established. Phosphatidylserine exposure after ischemia in the rabbit heart could be detected by radionuclide imaging with (99m)Tc-AA5. Pathologic characterization of the explanted rabbit hearts did not show apoptosis or necrosis. Homogenization and ultracentrifugation of the ischemic myocardial tissue from rabbit hearts recovered two thirds of the radiolabeled AA5 from the cytoplasmic compartment. Murine experiments demonstrated that the cardiomyocytes expressed phosphatidylserine on their cell surface after an ischemic insult of 5 min. Phosphatidylserine exposure occurred continuously for at least 6 h after solitary ischemic insult. AA5 targeted the exposed phosphatidylserine on cardiomyocytes; AA5 was internalized into cytoplasmic vesicles within 10-30 min. Twenty-four hours after ischemia, cardiomyocytes with internalized AA5 had restored phosphatidylserine asymmetry of the sarcolemma, and no detectable phosphatidylserine remained on the cell surface. The preadministration of a pan-caspase inhibitor, zVAD-fmk, prevented phosphatidylserine exposure after ischemia. After a single episode of ischemia, cardiomyocytes express phosphatidylserine, which is amenable to targeting by AA5, for at least 6 h. Phosphatidylserine exposure is transient and internalized in cytoplasmic vesicles after AA5 binding, indicating the reversibility of the apoptotic process.


Seasonal effects on gene expression, cleavage timing, and developmental competence of bovine preimplantation embryos.
We examined the association between season and expression of genes involved in early embryonic development with an emphasis on cleavage rate and timing of the first embryonic cleavage. In Exp. 1, oocytes were aspirated during the cold (Dec-Apr) and hot (May-Nov) seasons. Matured oocytes were chemically activated and cultured in vitro. The developmental peak to the two- and four-cell stages occurred earlier, with a higher proportion of first-cleaved embryos, during the cold season relative to the hot season (P<0.01). In Exp. 2, a time-lapse system was employed to characterize the delayed cleavage noted for the hot season. Cleavage to the two-cell stage occurred in two distinct waves: early cleavage occurred between 18 and 25 h post activation, and late cleavage occurred between 27 and 40 h post activation. In Exp. 3, oocytes were aspirated during the cold and hot seasons, matured in vitro, fertilized, and cultured for 8 days. In each season, early- and late-cleaved two-cell stage embryos were collected. Total RNA was isolated, and semi-quantitative and real-time PCRs were carried out with primers for GDF9, POU5F1, and GAPDH using 18S rRNA as the reference gene. In both seasons, the expression of all examined genes was higher (P<0.05) in early- versus late-cleaved embryos. POU5F1 expression was higher (P<0.05) in early-cleaved embryos developed in the cold season versus the hot season counterparts. The findings suggest a deleterious seasonal effect on oocyte developmental competence with delayed cleavage and variation in gene expression.


Mining single-cell time-series datasets with Time Course Inspector.
Thanks to recent advances in live cell imaging of biosensors, microscopy experiments can generate thousands of single-cell time-series. To identify sub-populations with distinct temporal behaviours that correspond to different cell fates, we developed Time Course Inspector (TCI)-a unique tool written in R/Shiny to combine time-series analysis with clustering. With TCI it is convenient to inspect time-series, plot different data views and remove outliers. TCI facilitates interactive exploration of various hierarchical clustering and cluster validation methods. We showcase TCI by analysing a single-cell signalling time-series dataset acquired using a fluorescent biosensor. https://github.com/pertzlab/shiny-timecourse-inspector. Supplementary data are available at Bioinformatics online.


Shot-noise-limited operation of a monomode high-cavity-finesse semiconductor laser for microwave photonics applications.
Shot-noise-limited laser operation over a wide spectral bandwidth is demonstrated by using a semiconductor active medium inserted into a high-Q external cavity. This approach ensures, with a compact design, a sufficiently long photon lifetime to reach the oscillation-relaxation-free class A regime. The laser relative intensity noise is limited to the shot-noise relative floor, -156 dB/Hz for a 1 mA detected photocurrent, over the 100 MHz to 18 GHz bandwidth. The optimization of the laser cavity is discussed, and convenient shot-noise-limited operation is shown to be a trade-off between the cavity length and laser mode filtering.


Neonatal cytochrome P450 CYP3A7: A comprehensive review of its role in development, disease, and xenobiotic metabolism.
The human cytochrome P450 CYP3A7, once thought to be an enzyme exclusive to fetal livers, has more recently been identified in neonates and developing infants as old as 24 months post-gestational age. CYP3A7 has been demonstrated to metabolize two endogenous compounds that are known to be important in the growth and development of the fetus and neonate, namely dehydroepiandrosterone sulfate (DHEA-S) and all-trans retinoic acid (atRA). In addition, it is also known to metabolize a variety of drugs and xenobiotics, albeit generally to a lesser extent relative to CYP3A4/5. CYP3A7 is an important component in the development and protection of the fetal liver and additionally plays a role in certain disease states, such as cancer and adrenal hyperplasia. Ultimately, a full understanding of the expression, regulation, and metabolic properties of CYP3A7 is needed to provide neonates with appropriate individualized pharmacotherapy. This article summarizes the current state of knowledge of CYP3A7, including its discovery, distribution, alleles, RNA splicing, expression and regulation, metabolic properties, substrates, and inhibitors.


Ischemia-induced cleavage of cadherins in NRK cells: evidence for a role of metalloproteinases.
Although ischemia has been shown to disrupt cell adhesion, the underlying molecular mechanism is unknown. In these studies, we adapted a model of ischemia-reperfusion to normal rat kidney (NRK) cells, examined disruption of the cadherin/catenin complex, and identified a role for matrix metalloproteinases (MMPs) in ischemia-induced cleavage of cadherins. In NRK cells, ischemia was induced by applying a thin layer of PBS solution supplemented with calcium and magnesium and a layer of mineral oil, which restricts exposure to oxygen. NRK cells exhibited extracellular 80-kDa and intracellular 40-kDa E-cadherin fragments after 4 h of ischemia, and at 6 h the expression of full-length E-cadherin decreased. While no fragments of N-cadherin, alpha-catenin, and gamma-catenin were observed at any time point, the detectable levels of these proteins decreased during ischemia. Ischemia was detected by an increase in pimonidazole adducts, as well as an increase in glucose transporter-1 protein expression. Ischemia did not decrease cell number, but there was a decrease in ATP levels. In addition, there was no evidence of cleaved caspase 3 or 9 during 6 h of ischemia. The MMP inhibitors GM-6001 and TAPI-O inhibited cleavage and/or loss of E- and N-cadherin protein expression. Tissue inhibitors of metalloproteinases (TIMP)-3 and to a lesser extent TIMP-2, but not TIMP-1, inhibit ischemic cleavage and/or loss of E- and N-cadherin. These results demonstrate that ischemia induces a selective metalloproteinase-dependent cleavage of E-cadherin and decrease in N-cadherin that are associated with a disruption of junctional contacts.


Simultaneous determination of cis- and trans-resveratrol in wines by capillary zone electrophoresis.
A capillary zone electrophoresis method for determining cis- and trans-resveratrol isomers is proposed. Optimal conditions for the quantitative separation were investigated. A background electrolyte solution consisting of 40 mM borate buffer adjusted to pH 9.5, hydrodynamic injection and 5 kV of separation voltage were used. Good linearity and precision were obtained for the two isomers. Detection limits of 0.06 mg L-1 for trans-resveratrol and 0.08 mg L-1 for cis-reveratrol were obtained. The developed method is rapid and sensitive and it has been applied to determine cis- and trans-resveratrol in several red wines. The samples were purified and enriched by passing them through a preconditioned C18 cartridge and eluting the isomers with acetonitrile-water (3 + 7).


Reduced quality of life when experiencing menstrual pain in women with primary dysmenorrhea.
Primary dysmenorrhea is the most common gynecological condition among women of reproductive age. Although dysmenorrhea has been reported to affect the ability of women to carry out daily activities, the impact of primary dysmenorrheic pain specifically on quality of life (QoL), has yet to be elucidated. We investigated whether QoL varies between women with and without severe primary dysmenorrhea, and whether QoL is impaired only during menstruation or also during pain-free phases of the menstrual cycle. Twelve women with severe primary dysmenorrhea and nine control women completed the quality of life enjoyment and satisfaction questionnaire (Q-LES-Q-SF) during menstruation and during the late follicular phase. Women with dysmenorrhea had a significant reduction in Q-LES-Q-SF scores (mean ± SD: 54 ± 18%, percentage of the total maximum possible score) when they were experiencing severe menstrual pain compared with their own pain-free follicular phase (80 ± 14%, p < 0.0001) and compared with controls during menstruation (81 ± 10%, p < 0.0001). They also rated their overall life satisfaction and contentment as poorer during menstruation. Severe menstrual pain associated with primary dysmenorrhea, therefore, impacts health-related of QoL.


N-acetylcysteine prevents cigarette smoke induced small airways alterations in rats.
This study investigated the effect of cigarette smoke exposure and the potential protection N-acetylcysteine (NAC) in rat lungs. Forty-eight rats were exposed to cigarette smoke (CS) for 10 weeks, without (CS group) or with (CS+NAC group) oral intake of NAC 200 mg x rat(-1) x day(-1), or to fresh air (Control). All rat lungs were assessed in terms of lung function, ventilation distribution (nitrogen, helium and sulphur hexafluoride phase III slopes), and morphometry (airway wall thickening of small, medium and large bronchi). The small bronchi, defined as the airways with an internal perimeter <1,000 microm showed significantly thicker airway walls in the CS than in the Control group. By contrast, no airway wall thickening was observed in the CS+NAC group with respect to Control. Except for decreased lung volumes and compliance in CS and CS+NAC groups, which were entirely attributable to smaller body weight gain, lung function was indistinguishable from Control. Phase III slopes were significantly increased only in the CS group. In conclusion, smoke-induced alterations in the rat lungs were reflected in wall thickening of the small bronchi and increased ventilation maldistribution. These smoke-induced morphometric and ventilation distribution alterations were prevented by N-acetylcysteine.


Candidate parasitic diseases.
This paper discusses five parasitic diseases: American trypanosomiasis (Chagas disease), dracunculiasis, lymphatic filariasis, onchocerciasis and schistosomiasis. The available technology and health infrastructures in developing countries permit the eradication of dracunculiasis and the elimination of lymphatic filariasis due to Wuchereria bancrofti. Blindness due to onchocerciasis and transmission of this disease will be prevented in eleven West African countries; transmission of Chagas disease will be interrupted. A well-coordinated international effort is required to ensure that scarce resources are not wasted, efforts are not duplicated, and planned national programmes are well supported.


Low-Temperature-Meltable Elastomers Based on Linear Polydimethylsiloxane Chains Alpha, Omega-Terminated with Mesogenic Groups as Physical Crosslinker: A Passive Smart Material with Potential as Viscoelastic Coupling. Part II-Viscoelastic and Rheological Properties.
Rheological and viscoelastic properties of physically crosslinked low-temperature elastomers were studied. The supramolecularly assembling copolymers consist of linear polydimethylsiloxane (PDMS) elastic chains terminated on both ends with mesogenic building blocks (LC) of azobenzene type. They are generally and also structurally highly different from the well-studied LC polymer networks or LC elastomers: The LC units make up only a small volume fraction in our materials and act as fairly efficient physical crosslinkers with thermotropic properties. The aggregation (nano-phase separation) of the relatively rare, small and spatially separated terminal LC units generates temperature-switched viscoelasticity in the molten copolymers. Their rheological behavior was found to be controlled by an interplay of nano-phase separation of the LC units (growth and splitting of their aggregates) and of the thermotropic transitions in these aggregates (which change their stiffness). As a consequence, multiple gel points (up to three) are observed in temperature scans of the copolymers. The physical crosslinks also can be reversibly disconnected by large mechanical strain in the 'warm' rubbery state, as well as in melt (thixotropy). The kinetics of crosslink formation was found to be fast if induced by temperature and extremely fast in case of internal self-healing after strain damage. Thixotropic loop tests hence display only very small hysteresis in the LC-melt-state, although the melts show very distinct shear thinning. Our study evaluates structure-property relationships in three homologous systems with elastic PDMS segments of different length (8.6, 16.3 and 64.4 repeat units). The studied copolymers might be of interest as passive smart materials, especially as temperature-controlled elastic/viscoelastic mechanical coupling.


Capillary electrophoretic and mass spectrometric analysis of a polydisperse fluorosurfactant.
A fluorosurfactant has been studied using capillary electrophoresis and mass spectrometry. The fluorosurfactant, FC134, can be used as a buffer additive in capillary electrophoresis in order to decrease wall adsorption of proteins and in micellar electrokinetic chromatography. However, it has been discovered that this fluorosurfactant is polydisperse, thus containing substances with different lengths and structures. In this work, the fluorosurfactant sample components were separated by capillary electrophoresis. An uncoated as well as a poly(vinyl alcohol)-coated capillary were used with running electrolytes containing methanol and acetic acid. Following the capillary electrophoretic separation, fractions were collected for further analysis by MALDI-MS. Non-fractionated samples were also analyzed both by MALDI-MS and by ESI-MS.


Effectiveness and safety of the oxytocin antagonist atosiban versus beta-adrenergic agonists in the treatment of preterm labour. The Worldwide Atosiban versus Beta-agonists Study Group.
To compare the effectiveness and safety of the oxytocin antagonist atosiban with conventional beta-adrenergic agonist (beta-agonist) therapy in the treatment of preterm labour. Three multinational, multicentre, double-blind, randomised, controlled trials. Setting Hospitals in Australia, Canada, Czech Republic, Denmark, France, Israel, Sweden, and the UK. Women diagnosed with preterm labour at 23-33 completed weeks of gestation. Seven hundred and forty-two women were randomised; 733 received atosiban (n = 363; intravenous (iv) bolus dose of 6.75 mg, then 300 microg/minute iv. for 3h and 100 microg/min iv thereafter) or beta-agonist (n = 379; ritodrine, salbutamol or terbutaline iv; dose titrated) for at least 18h and up to 48 hours. Uterine contraction rate, cervical dilatation and effacement were used to assess progression of labour. An all patients treated analysis, using the Cochran-Mantel-Haenszel test, was performed. Tocolytic effectiveness was assessed in terms of the number of women undelivered after 48 hours and seven days. Safety was assessed in terms of maternal side effects and neonatal morbidity. There were no significant differences between atosiban and beta-agonists in delaying delivery for 48h (88.1% vs 88.9%; P = 0.99) or seven days (79.7% versus 77.6%; P = 0.28). Tocolytic effectiveness was also similar in terms of mean [SD] gestational age at delivery (35.8 [3.9] weeks vs 35.5 [4.1] weeks) and mean [SD] birthweight (2,491 [813] g versus 2,461 [831] g). Maternal side effects, particularly cardiovascular adverse events (8.3% vs 81.2%, P < 0.001), were reported more frequently in women given beta-agonists, resulting in more treatment discontinuations due to side effects (1.1% vs 15.4%, P = 0.0001). No statistical differences in neonatal/infant outcomes were observed with either study medication. In the largest study of tocolytic therapy to date, atosiban was comparable in clinical effectiveness to conventional beta-agonist therapy, but was associated with fewer maternal cardiovascular side effects. We conclude that atosiban has clinical advantages over current tocolytic therapy.


The relative contributions of interface pressure, shear stress, and temperature on tissue ischemia: a cross-sectional pilot study.
Tissue ischemia is thought to play a major role in the development of pressure ulcers. Pressure, shear, and temperature are acknowledged contributors, but the relative magnitude of each factor is largely unknown. A cross-sectional pilot study was conducted on the sacrums of four healthy volunteers to estimate the relative contributions of each variable by systematically varying and assessing the resulting level of ischemia in the skin tissue. Using a repeated measures design, 21 combinations of temperature (28˚C, 32˚C, and 36˚C); pressure (0 kPa, 8.0 kPa, and 13.3 kPa), corresponding to 0 mm Hg, 60 mm Hg, and 100 mm Hg; and shear stress (0 kPa, 6.7 kPa, and 14.0 kPa), corresponding to 0 mm Hg, 50 mm Hg, and 100 mm Hg (practical testing values), were tested twice, for a total of 168 trials. Using laser Doppler flowmetry, the magnitude of post-load reactive hyperemia was used as an index of ischemia. Fixed Effects and Ranks linear regression models were developed to predict three different indices of reactive hyperemic magnitude with pressure, shear stress, and temperature as the variables. Pressure and temperature were always highly significant predictors of the extent of reactive hyperemia (P <0.0001 for Perfusion Area, peak minus baseline blood flow, and Normalized Peak blood flow), and the contributions of shear stress were insignificant (P = 0.5351 for Perfusion Area, P = 0.6403 for Peak minus Baseline blood flow, and P = 0.8941 for Normalized Peak blood flow). Depending upon the model, comparison of coefficients suggested that an increase of 1.0˚C contributes as much to reactive hyperemia in the skin as 12 mm Hg to 15 mm Hg of interface pressure (coefficient ratios of temperature/pressure are 14.33 for Perfusion Area, 11.77 for Peak minus Baseline, and 12.97 for Normalized Peak, respectively). The findings also indicate that post-load metabolic repayment varied with temperature only at higher pressures, suggesting protective vasodilation was able to keep pace with mild compression. If confirmed in subsequent studies, the results suggest that managing both skin pressure and temperature may reduce the risk of ischemia.


A novel highly active AgMOF-based silver single-atom catalyst and its application to the aptamer SERS/RRS for the determination of aflatoxin B1.
A novel highly active silver single-atom catalyst (AgSAC) was prepared by a microwave-assisted solvothermal method using silver covalent organic frameworks (AgMOF) as precursors. It was characterized by transmission electron microscopy (TEM), X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS), infrared (IR), and surface-enhanced Raman scattering (SERS). The experiment found that AgSAC has excellent catalytic performance and can heavily catalyze the nano-reaction of chloroauric acid-malic acid (HAuCl4-H2Mi) to generate gold nanoparticles (AuNPs). The produced AuNPs have strong SERS, resonance Rayleigh scattering (RRS) and surface plasmon resonance absorption (Abs) signals. Aflatoxin B1 aptamer (AptAFB1) can be adsorbed to the surface of AgSAC through electrostatic interaction, to reduce the catalytic activity of AgSAC and the SERS/RRS/Abs signal of the system. When the target molecule (AFB1) was added, it will specifically bind to AptAFB1 and release AgSAC, restoring the catalytic activity of AgSAC, thereby restoring the SERS/RRS/Abs signal of the system. Based on this, a simple and sensitive aptamer sensing analysis platform for trace AFB1 was established, and a reasonable catalytic amplification mechanism of AgSAC was proposed. The SERS method exhibited the highest sensitivity, with a linear range of 0.005-0.225 μg/L and a detection limit of 0.002 μg/L.


Risk assessment in the 21st century: roadmap and matrix.
Abstract The RISK21 integrated evaluation strategy is a problem formulation-based exposure-driven risk assessment roadmap that takes advantage of existing information to graphically represent the intersection of exposure and toxicity data on a highly visual matrix. This paper describes in detail the process for using the roadmap and matrix. The purpose of this methodology is to optimize the use of prior information and testing resources (animals, time, facilities, and personnel) to efficiently and transparently reach a risk and/or safety determination. Based on the particular problem, exposure and toxicity data should have sufficient precision to make such a decision. Estimates of exposure and toxicity, bounded by variability and/or uncertainty, are plotted on the X- and Y-axes of the RISK21 matrix, respectively. The resulting intersection is a highly visual representation of estimated risk. Decisions can then be made to increase precision in the exposure or toxicity estimates or declare that the available information is sufficient. RISK21 represents a step forward in the goal to introduce new methodologies into 21st century risk assessment. Indeed, because of its transparent and visual process, RISK21 has the potential to widen the scope of risk communication beyond those with technical expertise.


Molecular analysis of mammalian timeless.
We cloned the mouse cDNA of a mammalian homolog of the Drosophila timeless (tim) gene and designated it mTim. The mTim protein shows five homologous regions with Drosophila TIM. mTim is weakly expressed in the suprachiasmatic nuclei (SCN) but exhibits robust expression in the hypophyseal pars tuberalis (PT). mTim RNA levels do not oscillate in the SCN nor are they acutely altered by light exposure during subjective night. mTim RNA is expressed at low levels in several peripheral tissues, including eyes, and is heavily expressed in spleen and testis. Yeast two-hybrid assays revealed an array of interactions between the various mPER proteins but no mPER-mTIM interactions. The data suggest that PER-PER interactions have replaced the function of PER-TIM dimers in the molecular workings of the mammalian circadian clock.


Outcomes after orthopedic trauma.
Clinical orthopedic research needs better ability to assess patient expectations with regard to orthopedic trauma surgery outcomes. The aim of this study was to investigate to which extent patient expectations prior to surgery could be met after surgery. Patients (≥18 years) with surgical ankle fractures were prospectively recruited at 5 orthopedic trauma clinics in the United States (USA), Canada, and Brazil and followed up for 12 months. Patients were asked to complete a previously validated trauma expectation factor (TEF) questionnaire prior to surgery and a trauma outcome measure (TOM) 1 year after surgery. At 1 year, 155 patients had provided complete records. Almost half (49%; 76/155) had a 1-year TOM score equaling or exceeding their preoperative TEF score (95% CI: 41-57%). The remaining scores failed to meet patient expectations. TOM scores matched or exceeded patient expectations for 33% of patients in the USA and 47% in Canada, but for 69% in Brazil ( p = 0.001 (USA); p = 0.024 (Canada)). This geographical effect was attributable to higher patient expectations in North America as compared to Brazil (average TEF scores: 36 (North America) versus 31 (Brazil); p < 0.001). Patients with lower household income or smokers were more likely to be satisfied with their treatment ( p = 0.02 and p = 0.05, respectively). Furthermore, patients with severe type C fractures had better rates of satisfaction (62%) than patients with simpler B (50%) or type A fractures (33%) ( p = 0.01 [C type versus A type]). Orthopedic surgeons have difficulty in meeting or exceeding presurgical patient expectations of long-term outcomes for ankle fracture surgery. This study provides evidence that culture, geography, and surgeon-patient communication have considerable influence on patient expectations.


Keratitis After Post-Kala-Azar Dermal Leishmaniasis.
To report 2 cases of keratitis occurring after post-kala-azar dermal leishmaniasis (PKDL) in immunocompetent patients. Case report and literature review. Two male patients presented with a dense stromal infiltrate in the temporal and superior aspects of the cornea, respectively. Microbiological workup in both patients did not show any offending organism. Both patients were undergoing treatment for PKDL in the form of oral miltefosine. After careful deliberation, topical prednisolone was started under antibiotic cover for both patients with close follow-up. There was a dramatic improvement with resolution of the infiltrate and a good visual outcome. We present the first reported cases of keratitis after PKDL, which responded to topical corticosteroid therapy. The treating clinician must be made aware of such a presentation of leishmaniasis especially in endemic areas.


Predicting the acid/base behavior of proteins: a constant-pH Monte Carlo approach with generalized born solvent.
The acid/base properties of proteins are essential in biochemistry, and proton binding is a valuable reporter on electrostatic interactions. We propose a constant-pH Monte Carlo strategy to compute protonation free energies and pK(a)'s. The solvent is described implicitly, through a generalized Born model. The electronic polarizability and backbone motions of the protein are included through the protein dielectric constant. Side chain motions are described explicitly, by the Monte Carlo scheme. An efficient computational algorithm is described, which allows us to treat the fluctuating shape of the protein/solvent boundary in a way that is numerically exact (within the GB framework); this contrasts with several previous constant-pH approaches. For a test set of six proteins and 78 titratable groups, the model performs well, with an rms error of 1.2 pH units. While this is slightly greater than a simple Null model (rms error of 1.1) and a fully empirical model (rms error of 0.9), it is obtained using physically meaningful model parameters, including a low protein dielectric of four. Importantly, similar performance is obtained for side chains with large and small pK(a) shifts (relative to a standard model compound). The titration curve slopes and the conformations sampled are reasonable. Several directions to improve the method further are discussed.


Waist circumference and BMI in relation to serum high sensitivity C-reactive protein (hs-CRP) in Cuban Americans with and without type 2 diabetes.
Relationship between high-sensitivity C-reactive protein (hs-CRP) and adiposity by diabetes status and gender in Cuban-Americans with and without type 2 diabetes (T2D) was studied. Adult subjects, 226 females, 129 males participated in a case control, single time point study. Subjects with T2D were older, had higher waist circumference (WC) and body mass index (BMI). WC and BMI were associated with ln hs-CRP (P < 0.001). An interaction with diabetes status was found for BMI (P = 0.037). Gender showed a strong relationship with ln hs-CRP (P < 0.001), which was moderated by diabetes status. Only males without diabetes exhibited a significant relationship for both WC and BMI with ln hs-CRP. In this sample of Cuban-Americans, WC and BMI had stronger associations with ln hs-CRP but not with diabetes status. Obesity prevention and controlling for CRP levels may be necessary to eliminate its contributions to develop diabetes and cardiovascular disease (CVD).


A Ropy Exopolysaccharide-Producing Strain Bifidobacterium pseudocatenulatum Bi-OTA128 Alleviates Dextran Sulfate Sodium-Induced Colitis in Mice.
Inflammatory bowel disease (IBD) is a chronic disease associated with overactive inflammation and gut dysbiosis. Owing to the beneficial effects of bifidobacteria on IBD treatment, this study aimed to investigate the anti-inflammation effects of an exopolysaccharide (EPS)-producing strain Bifidobacterium pseudocatenulatum Bi-OTA128 through a dextran sulfate sodium (DSS)-induced colitis mice model. B. pseudocatenulatum treatment improved DSS-induced colitis symptoms and maintained intestinal barrier integrity by up-regulating MUC2 and tight junctions' expression. The oxidative stress was reduced after B. pseudocatenulatum treatment by increasing the antioxidant enzymes of SOD, CAT, and GSH-Px in colon tissues. Moreover, the overactive inflammatory responses were also inhibited by decreasing the pro-inflammatory cytokines of TNF-α, IL-1β, and IL-6, but increasing the anti-inflammatory cytokine of IL-10. The EPS-producing strain Bi-OTA128 showed better effects than that of a non-EPS-producing stain BLYR01-7 in modulating DSS-induced gut dysbiosis. The Bi-OTA128 treatment increased the relative abundance of beneficial bacteria Bifidobacterium and decreased the maleficent bacteria Escherichia-Shigella, Enterorhabuds, Enterobacter, and Osillibacter associated with intestinal inflammation. Notably, the genera Clostridium sensu stricto were only enriched in Bi-OTA128-treated mice, which could degrade polysaccharides to produce acetic acid and butyrate in the gut. This finding demonstrated a cross-feeding effect induced by the EPS-producing strain in gut microbiota. Collectively, these results highlighted the anti-inflammatory effects of the EPS-producing strain B. pseudocatenulatum Bi-OTA128 on DSS-induced colitis, which could be used as a candidate probiotic supporting recovery from ongoing colitis.


Relationship status and perceived support in the social regulation of neural responses to threat.
Strong social ties correspond with better health and well being, but the neural mechanisms linking social contact to health remain speculative. This study extends work on the social regulation of brain activity by supportive handholding in 110 participants (51 female) of diverse racial and socioeconomic origins. In addition to main effects of social regulation by handholding, we assessed the moderating effects of both perceived social support and relationship status (married, cohabiting, dating or platonic friends). Results suggest that, under threat of shock, handholding by familiar relational partners attenuates both subjective distress and activity in a network associated with salience, vigilance and regulatory self-control. Moreover, greater perceived social support corresponded with less brain activity in an extended network associated with similar processes, but only during partner handholding. In contrast, we did not observe any regulatory effects of handholding by strangers, and relationship status did not moderate the regulatory effects of partner handholding. These findings suggest that contact with a familiar relational partner is likely to attenuate subjective distress and a variety of neural responses associated with the presence of threat. This effect is likely enhanced by an individual's expectation of the availability of support from their wider social network.


Fertility effects of the abolition of legal abortion in Romania.
Abstract There is much interest to-day in governmental actions and regulations designed to have an effect on fertility. Widespread concern with the implications of population growth has led to unprecedented attention to the design and implementation of governmental policies intended to affect fertility. Unfortunately, there is very little empirical evidence of the effect of governmental action, largely because of the difficulty of interpreting the causal relations between changes in laws or programmes on the one hand, and fertility trends on the other. For this reason, the drastic alteration of the fertility laws in Romania in 1966 is of special interest in that it provides something approaching an experimental context for examining the effect of a legal code on fertility.


Epicatechin-3-Gallate Signaling and Protection against Cardiac Ischemia/Reperfusion Injury.
At concentrations found in humans after ingestion of one to two cups of green tea, epicatechin-3-gallate (ECG) modulates Na/K-ATPase conformation and activity. Akin to ouabain, an archetypal Na/K-ATPase ligand of the cardiotonic steroid (CTS) family, ECG also activates protein kinase C epsilon type (PKCε) translocation and increases the force of contraction of the rat heart. This study evaluated whether, like ouabain, ECG also modulates Na/K-ATPase/Src receptor function and triggers pre- and postconditioning against ischemia/reperfusion (I/R) injury. In vitro, ECG activated the purified Na/K-ATPase/Src complex. In Langendorff-perfused rat hearts, submicromolar concentrations of ECG administered either before or after ischemia reduced infarct size by more than 40%, decreased lactate dehydrogenase release, and improved the recovery of cardiac function. ECG protection was blocked by PKCε inhibition and attenuated by mitochondrial KATP channel inhibition. In a unique mammalian cell system with depleted Na/K-ATPase α1 expression, ECG-induced PKCε activation persisted but protection against I/R was blunted. Taken together, these results reveal a Na/K-ATPase- and PKCε-dependent mechanism of protection by ECG that is also distinct from the mechanism of action of ouabain. These ECG properties likely contribute to the positive impact of green tea consumption on cardiovaascular health and warrant further investigation into the role of cardiac Na/K-ATPase signaling in the cardioprotective effect of green tea consumption. SIGNIFICANCE STATEMENT: Consumption of green tea, the richest dietary source of ECG, is associated with a reduced risk of cardiac mortality. Antioxidant effects of ECG and other tea polyphenols are well known, but reported for concentrations well above dietary levels. Therefore, the mechanism underlying the cardioprotective effect of green tea remains incompletely understood. This study provides experimental evidence that ECG concentrations commonly detected in humans after consumption of a cup of tea trigger the Na/K-ATPase/Src receptor in a cell-free system, activate a CTS-like signaling pathway, and provide PKCε-dependent protection against ischemia/reperfusion injury in rat hearts. Mechanistic studies in mammalian cells with targeted Na/K-ATPase depletion revealed that although Na/K-ATPase does not mediate ECG-induced PKCε activation, it is required for ECG-induced protection against ischemia/reperfusion injury.


Spontaneous Otoacoustic Emissions in TectaY1870C/+ Mice Reflect Changes in Cochlear Amplification and How It Is Controlled by the Tectorial Membrane.
Spontaneous otoacoustic emissions (SOAEs) recorded from the ear canal in the absence of sound reflect cochlear amplification, an outer hair cell (OHC) process required for the extraordinary sensitivity and frequency selectivity of mammalian hearing. Although wild-type mice rarely emit, those with mutations that influence the tectorial membrane (TM) show an incidence of SOAEs similar to that in humans. In this report, we characterized mice with a missense mutation in Tecta, a gene required for the formation of the striated-sheet matrix within the core of the TM. Mice heterozygous for the Y1870C mutation (TectaY1870C/+ ) are prolific emitters, despite a moderate hearing loss. Additionally, Kimura's membrane, into which the OHC stereocilia insert, separates from the main body of the TM, except at apical cochlear locations. Multimodal SOAEs are also observed in TectaY1870C/+ mice where energy is present at frequencies that are integer multiples of a lower-frequency SOAE (the primary). Second-harmonic SOAEs, at twice the frequency of a lower-frequency primary, are the most frequently observed. These secondary SOAEs are found in spatial regions where stimulus-evoked OAEs are small or in the noise floor. Introduction of high-level suppressors just above the primary SOAE frequency reduce or eliminate both primary and second-harmonic SOAEs. In contrast, second-harmonic SOAEs are not affected by suppressors, either above or below the second-harmonic SOAE frequency, even when they are much larger in amplitude. Hence, second-harmonic SOAEs do not appear to be spatially separated from their primaries, a finding that has implications for cochlear mechanics and the consequences of changes to TM structure.


Functional mimics of glutathione peroxidase: bioinspired synthetic antioxidants.
Oxidative stress is caused by an imbalance between the production of reactive oxygen species (ROS) and the biological system's ability to detoxify these reactive intermediates. Mammalian cells have elaborate antioxidant defense mechanisms to control the damaging effects of ROS. Glutathione peroxidase (GPx), a selenoenzyme, plays a key role in protecting the organism from oxidative damage by catalyzing the reduction of harmful hydroperoxides with thiol cofactors. The selenocysteine residue at the active site forms a "catalytic triad" with tryptophan and glutamine, which activates the selenium moiety for an efficient reduction of peroxides. After the discovery that ebselen, a synthetic organoselenium compound, mimics the catalytic activity of GPx both in vitro and in vivo, several research groups developed a number of small-molecule selenium compounds as functional mimics of GPx, either by modifying the basic structure of ebselen or by incorporating some structural features of the native enzyme. The synthetic mimics reported in the literature can be classified in three major categories: (i) cyclic selenenyl amides having a Se-N bond, (ii) diaryl diselenides, and (iii) aromatic or aliphatic monoselenides. Recent studies show that ebselen exhibits very poor GPx activity when aryl or benzylic thiols such as PhSH or BnSH are used as cosubstrates. Because the catalytic activity of each GPx mimic largely depends on the thiol cosubstrates used, the difference in the thiols causes the discrepancies observed in different studies. In this Account, we demonstrate the effect of amide and amine substituents on the GPx activity of various organoselenium compounds. The existence of strong Se···O/N interactions in the selenenyl sulfide intermediates significantly reduces the GPx activity. These interactions facilitate an attack of thiol at selenium rather than at sulfur, leading to thiol exchange reactions that hamper the formation of catalytically active selenol. Therefore, any substituent capable of enhancing the nucleophilic attack of thiol at sulfur in the selenenyl sulfide state would enhance the antioxidant potency of organoselenium compounds. Interestingly, replacement of the sec-amide substituent by a tert-amide group leads to a weakening of Se···O interactions in the selenenyl sulfide intermediates. This modification results in 10- to 20-fold enhancements in the catalytic activities. Another strategy involving the replacement of tert-amide moieties by tert-amino substituents further increases the activity by 3- to 4-fold. The most effective modification so far in benzylamine-based GPx mimics appears to be either the replacement of a tert-amino substituent by a sec-amino group or the introduction of an additional 6-methoxy group in the phenyl ring. These strategies can contribute to a remarkable enhancement in the GPx activity. In addition to enhancing catalytic activity, a change in the substituents near the selenium moiety alters the catalytic mechanisms. The mechanistic investigations of functional mimics are useful not only for understanding the complex chemistry at the active site of GPx but also for designing and synthesizing novel antioxidants and anti-inflammatory agents.


Minimally Invasive Laser Treatment of Ureterocele.
Introduction: Ureterocelemay cause severe pyelo-ureteral obstruction with afebrile urinary tract infections in infants and children. Early decompressive treatment is advocated to reduce the risk of related renal and urinary tract damage. Endoscopic techniques of incision have been offered utilizing diathermic electrode. We adopted laser energy to release the obstruction of the ureterocele and reduce the need of further surgery. Our technique is described and results are presented, compared with a group of matched patients treated by diathermic energy. Materials and methods: Decompression was performed by endoscopic multiple punctures at the basis of the ureterocele. Holmium YAG Laser was utilized with 0.5-0.8 joule energy, through 8-9.8F cystoscope under general anesthesia. The control group received ureterocele incision by diathermic energy through pediatric resettoscope. Foley indwelling catheter was removed after 18-24 h. Renal ultrasound was performed at 1, 3, 6, and 12 months follow-up. Voiding cysto-urethrogram and radionuclide renal scan were done at 6-18 months in selected cases. Statistical analysis was utilized for data evaluation. Results: From January 2012 to December 2017, 64 endoscopic procedures were performed: 49 were ectopic and 15 orthotopicureteroceles. Fifty-three were in duplex systems, mostly ectopic. Mean age at endoscopy was 6.3 months (1-168). Immediate decompression of the ureterocele was obtained, but in five cases (8%) a second endoscopic puncture was necessary at 6-18 months follow-up for recurrent dilatation. Urinary tract infections and de novo refluxes occurred in 23.4 and 29.7% in the study group, compared to 38.5 and 61.5% in the 26 controls (p < 0.05). Further surgery was required in 12 patients (18%) at 1-5 years follow-up (10 in ectopic ureteroceles with duplex systems): seven ureteral reimplantation for reflux, five laparoscopic hemy-nephro-ureterectomy. Orthotopic ureteroceceles had better outcome. Secondary surgery was necessary in 13 patients (50.0%) of control group (p < 0.05). Conclusions: Early endoscopic decompression should be considered first line treatment of obstructing ureterocele in infants and children. Multiple punctures at the basis of the ureterocele, performed by low laser energy, is resulted a really minimally invasive treatment, providing immediate decompression of the upper urinary tract, and reducing the risk of further aggressive surgery.


Prophage induction of noninducible coliphage 186.
Coliphage 186 has been regarded as a member of the noninducible group of coliphages. Evidence that prophage 186 is induced by ultraviolet irradiation or by treatment with nalidixic acid or mitomycin C is now presented. The phage yields were similar to those from lysogens of the inducible phage lambda, and the induction required a recA(+) host. A noninducible mutant of 186 was isolated from its heat-inducible derivative, 186cIts, that was no longer inducible by ultraviolet irradiation but remained heat inducible. That zygotic induction of 186 after transfer from a lysogenic male to a non-lysogenic recipient did not occur is indicated by the following findings: (i) there was only a slight increase in phage titer; (ii) similar levels of recombinants were obtained for markers adjacent or distal to the phage integration site, whether the recipient was lysogenic or not, and there was no effect on the gradient of marker transfer; (iii) lysogenic recombinants were readily found and the co-transfer of 186 with adjacent markers was the same to lysogenic or non-lysogenic recipients. Thus, 186 formed an inducible prophage that did not display zygotic induction. Nevertheless, it shared many properties with the noninducible phage P2 as outlined in the discussion.


Role of interleukin-22 in tuberculosis patients.
Disease progression of tuberculosis (TB) depends on the balance between the microorganism's virulence and the host defense systems (mainly T cell-mediated immune response). Interleukin-22 (IL-22) helps in cell proliferation and regeneration and provides protection against microbial diseases. The IL-22-producing T cells can migrate into the granulomas during TB infection. However, disparity exists in literature regarding its role. The present study aims to compare serum IL-22 levels and its' expression in TB patients and healthy controls. 87 TB patients and 85 healthy subjects were enrolled in the study. Under aseptic conditions, venous blood was withdrawn. Serum IL-22 levels were estimated using enzyme-linked immunosorbent assay, and its gene expression was assessed using SYBR green-based quantitative PCR technology. A statistical analysis was performed using SPSS. The median (interquartile range) of serum IL-22 levels was significantly lower in TB patients (18.55 (5.08) pg/mL) when compared to controls (49.38 (162.88) pg/mL) (p<0.0001). The IL-22 expression was significantly upregulated with a fold change value of 29.44 in TB patients. The IL-22 levels were found to be significantly decreased in patients, contradictory to its expression, which is upregulated. It plays a crucial role for the modulation of tissues in response to TB infection.


Reduction of hydrophilic ubiquinones by the flavin in mitochondrial NADH:ubiquinone oxidoreductase (Complex I) and production of reactive oxygen species.
NADH:ubiquinone oxidoreductase (complex I) from bovine heart mitochondria is a complicated, energy-transducing, membrane-bound enzyme that contains 45 different subunits, a non-covalently bound flavin mononucleotide, and eight iron-sulfur clusters. The mechanisms of NADH oxidation and intramolecular electron transfer by complex I are gradually being defined, but the mechanism linking ubiquinone reduction to proton translocation remains unknown. Studies of ubiquinone reduction by isolated complex I are problematic because the extremely hydrophobic natural substrate, ubiquinone-10, must be substituted with a relatively hydrophilic analogue (such as ubiquinone-1). Hydrophilic ubiquinones are reduced by an additional, non-energy-transducing pathway (which is insensitive to inhibitors such as rotenone and piericidin A). Here, we show that inhibitor-insensitive ubiquinone reduction occurs by a ping-pong type mechanism, catalyzed by the flavin mononucleotide cofactor in the active site for NADH oxidation. Moreover, semiquinones produced at the flavin site initiate redox cycling reactions with molecular oxygen, producing superoxide radicals and hydrogen peroxide. The ubiquinone reactant is regenerated, so the NADH:Q reaction becomes superstoichiometric. Idebenone, an artificial ubiquinone showing promise in the treatment of Friedreich's Ataxia, reacts at the flavin site. The factors which determine the balance of reactivity between the two sites of ubiquinone reduction (the energy-transducing site and the flavin site) and the implications for mechanistic studies of ubiquinone reduction by complex I are discussed. Finally, the possibility that the flavin site in complex I catalyzes redox cycling reactions with a wide range of compounds, some of which are important in pharmacology and toxicology, is discussed.


Evaluation of aortic stenosis severity using 4D flow jet shear layer detection for the measurement of valve effective orifice area.
The objective of this study was to evaluate the potential of 4D flow MRI to assess valve effective orifice area (EOA) in patients with aortic stenosis as determined by the jet shear layer detection (JSLD) method. An in-vitro stenosis phantom was used for validation and in-vivo imaging was performed in 10 healthy controls and 40 patients with aortic stenosis. EOA was calculated by the JSLD method using standard 2D phase contrast MRI (PC-MRI) and 4D flow MRI measurements (EOAJSLD-2D and EOAJSLD-4D, respectively). As a reference standard, the continuity equation was used to calculate EOA (EOACE) with the 2D PC-MRI velocity field and compared to the EOAJSLD measurements. The in-vitro results exhibited excellent agreement between flow theory (EOA=0.78cm(2)) and experimental measurement (EOAJSLD-4D=0.78±0.01cm(2)) for peak velocities ranging from 0.9 to 3.7m/s. In-vivo results showed good correlation and agreement between EOAJSLD-2D and EOACE (r=0.91, p<0.001; bias: -0.01±0.38cm(2); agreement limits: 0.75 to -0.77cm(2)), and between EOAJSLD-4D and EOACE (r=0.95, p<0.001; bias: -0.09±0.26cm(2); limits: 0.43 to -0.62cm(2)). This study demonstrates the feasibility of measuring EOAJSLD using 4D flow MRI. The technique allows for optimization of the EOA measurement position by visualizing the 3D vena contracta, and avoids potential sources of EOACE measurement variability.


Effects of a Mentor Program for Coaches on the Coach-Athlete Relationship.
The present study was designed to explore the effects of a one-year coach education program on coaches' perceptions of their communication skills and co-orientation of their coach-athlete relationships. The study was designed with an experimental group and a control group. The experiment group consisted of 66 coaches (and 295 athletes) who received formal mentoring and the control group consisted of 41 coaches (and 148 athletes) who did not receive any mentoring. Data were analysed using structural equation modelling with autoregressive cross-lagged analysis. Results from the self-reported questionnaire at pre-test and post-test showed that the reciprocity of the coach-athlete relationships was not statistically significant. However, coaches' experience of change in attention skills from the pre-test to the post-test positively predicted changes in their own perception of the coach-athlete relationship, whereas this association was not significant in the athletes' perceptions. Moreover, the coach education programme increased coaches' perception of their relational bonds with their athletes, but this increase did not correspond with an increase in athletes' perception of the relational bonds with their coach. Practical implications and suggestions for further research are discussed in light of these findings.


Mutagenesis of putative ciliary genes with the CRISPR/Cas9 system in zebrafish identifies genes required for retinal development.
Cilia are conserved microtubule-based organelles that function as mechanical and chemical sensors in various cell types. By bioinformatic, genomic, and proteomic studies, more than 2000 proteins have been identified as cilium-associated proteins or putative ciliary proteins; these proteins are referred to as the ciliary proteome or the ciliome. However, little is known about the function of these numerous putative ciliary proteins in cilia. To identify the possible new functional proteins or pathways in cilia, we carried out a small-scale genetic screen targeting 54 putative ciliary genes by using the clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9 (CRISPR/Cas9) system. We successfully constructed 54 zebrafish mutants, and 8 of them displayed microphthalmias. Three of these 8 genes encode proteins for protein transport, suggesting the important roles of protein transport in retinal development. In situ hybridization revealed that all these genes are expressed in zebrafish eyes. Furthermore, polo-like kinase 1 was required for ciliogenesis in neural tube. We uncovered the potential function of the ciliary genes for the retinal development of zebrafish.-Hu, R., Huang, W., Liu, J., Jin, M., Wu, Y., Li, J., Wang, J., Yu, Z., Wang, H., Cao, Y. Mutagenesis of putative ciliary genes with the CRISPR/Cas9 system in zebrafish identifies genes required for retinal development.


Solar inactivated Vibrio cholerae induces maturation of JAWS II dendritic cell line in vitro.
Solar disinfection (SODIS) has been shown to reduce the risk associated with the contraction of water borne diseases such as cholera. However, little or no research has been undertaken in exploring the role played by the immune system following the consumption of solar inactivated water pathogens. This study investigated the potential for solar inactivated Vibrio cholerae to induce the maturation of dendritic cells in vitro. Dendritic cells are professional antigen presenting cells found in mammals. However, only in their mature form are dendritic cells able to play their role towards a long lasting immune response. Three strains of V. cholerae were solar irradiated for 7 hours. Thereafter, the solar irradiated, non-solar irradiated, phosphate buffered saline prepared and heat/chemically inactivated cultures of V. cholerae as well as lipopolysaccharide and cholerae toxin-β subunit were used to stimulate immature dendritic cells. After 48 hours, the dendritic cells were assessed for the expression of CD54, CD80, CD83, CD86, MHC-I and MHC-II cell surface markers. Results show that solar inactivated V. cholerae was able to induce maturation of the dendritic cells in vitro. These findings suggest that there may be an immunological benefit in consuming SODIS treated water.


A case of craniopagus parasiticus: an antenatal diagnosis by ultrasound screening at 16 weeks of gestation and a literature review of recently reported cases.
Al Yaqoubi HN, Fatema N, Al Fahdi BS. A case of craniopagus parasiticus: an antenatal diagnosis by ultrasound screening at 16 weeks of gestation and a literature review of recently reported cases. Turk J Pediatr 2019; 61: 941-945. Craniopagus parasiticus (CP) is a rare type of malformation of conjoined twins, with one degenerated or underdeveloped parasite twin united at the cranium with the other fully developed twin. Only a handful of cases have been documented in the literature to date. The incidence of this rare deformity is approximately 4 to 6 out of every 10,000,000 live births. We report on a case of CP, diagnosed at 16 weeks of gestation by ultrasound screening. To the best of our knowledge, the case that we present is the first CP case that was diagnosed at such an early gestational age. The formed fetus was found to harbour complex cardiac anomalies. In view of poor prognosis of survival after delivery and upon permission from the couple, the pregnancy was terminated at 17 weeks of gestation.


Dabigatran abrogates brain endothelial cell permeability in response to thrombin.
Atrial fibrillation (AF) increases the risk and severity of thromboembolic stroke. Generally, antithrombotic agents increase the hemorrhagic risk of thromboembolic stroke. However, significant reductions in thromboembolism and intracerebral hemorrhage have been shown with the antithrombin dabigatran compared with warfarin. As thrombin has been implicated in microvessel injury during cerebral ischemia, we hypothesized that dabigatran decreases the risk of intracerebral hemorrhage by direct inhibition of the thrombin-mediated increase in cerebral endothelial cell permeability. Primary murine brain endothelial cells (mBECs) were exposed to murine thrombin before measuring permeability to 4-kDa fluorescein isothiocyanate-dextran. Thrombin increased mBEC permeability in a concentration-dependent manner, without significant endothelial cell death. Pretreatment of mBECs with dabigatran completely abrogated the effect of thrombin on permeability. Neither the expressions of the endothelial cell β1-integrins nor the tight junction protein claudin-5 were affected by thrombin exposure. Oxygen-glucose deprivation (OGD) also increased permeability; this effect was abrogated by treatment with dabigatran, as was the additive effect of thrombin and OGD on permeability. Taken together, these results indicate that dabigatran could contribute to a lower risk of intracerebral hemorrhage during embolism-associated ischemia from AF by protection of the microvessel permeability barrier from local thrombin challenge.


Autoantibodies against small nuclear ribonucleoprotein components.
Sera from patients with systemic rheumatic diseases often contain antibodies against nuclear antigens. Among these are proteins complexed with the small nuclear RNA (snRNA) U1, U2, U4, U5 and U6. In human cells, at least 11 different polypeptides (called 70K, A, A', B', B", B, C, D, E, F and G) ranging in molecular weight from 70 to 11 kDa, are associated with the snRNA, constituting the snRNP particles. In this report characteristics of 3 classes of autoantibodies are described. Anti-(U1) RNP antibodies recognize the U1 specific 70K and/or A and/or C proteins. Anti-Sm antibodies recognize proteins associated with all U snRNA, primarily the B', B and D proteins. Anti-(U1,U2) RNP sera contain antibodies directed against the U2 specific A' or B" proteins. These antibodies are useful tools for studying the structure and function of U snRNP complexes. Using mutant U2 snRNA and monospecific antibodies directed against the U2 specific proteins, we analyzed the interactions between proteins and RNA in the U2 snRNP particle. We have also isolated recombinant clones containing cDNA of mRNA coding for a number of snRNA associated proteins. Possible directions of future research are discussed.


Xenoantigenicity of porcine decellularized valves.
The xenoantigenicity of porcine bioprosthetic valves is implicated as an etiology leading to calcification and subsequent valve failure. Decellularization of porcine valves theoretically could erase the antigenicity of the tissue leading to more durable prosthetic valves, but the effectiveness of decellularization protocols in regard to completely removing antigens has yet to be verified. Our hypothesis was that decellularization would remove the more abundant α-gal antigens but not remove all the non α-gal antigens, which could mount a response. Porcine aortic valves were decellularized with 1% sodium dodecyl sulfate for 4 days. Decellularized cusps were evaluated for α-gal epitopes by ELISA. To test for non α-gal antigens, valves were implanted into sheep. Serum was obtained from the sheep preoperatively and 1 week, 1 month, and 2 months postoperatively. This serum was utilized for anti-porcine antibody staining and for quantification of anti-pig IgM and IgG antibodies and complement. Decellularized porcine cusps had 2.8 ± 2.0% relative α-gal epitope as compared to fresh porcine aortic valve cusps and was not statistically significantly different (p = 0.4) from the human aortic valve cusp which had a 2.0 ± 0.4% relative concentration. Anti-pig IgM and IgG increased postoperatively from baseline levels. Preoperatively anti-pig IgM was 27.7 ± 1.7 μg/mL and it increased to 71.9 ± 12.1 μg/mL average of all time points postoperatively (p = 0.04). Preoperatively anti-pig IgG in sheep serum was 44.9 ± 1.5 μg/mL and it increased to 72.6 ± 6.0 μg/mL average of all time points postoperatively (p = 0.01). There was a statistically significant difference (p = 0.00007) in the serum C1q concentration before valve implantation (2.5 ± 0.2 IU/mL) and at averaged time points after valve implantation (5.3 ± 0.3 IU/mL). Decellularization with 1% sodium dodecyl sulfate does not fully eliminate non α-gal antigens; however, significant reduction in α-gal presence on decellularized cusps was observed. Clinical implications of the non α-gal antigenic response are yet to be determined. As such, evaluation of any novel decellularized xenografts must include rigorous antigen testing prior to human trials.


Hybrid multi-layer displays providing accommodation cues.
Hybrid multi-layer displays are proposed as the system combines additive light field (LF) displays and multiplicative LF displays. The system is implemented by integrating the multiplicative LF displays with a half mirror to expand the overall depth of field. The hybrid displays are advantageous in that the form factor is competitive with existing additive LF displays with 2 layers implemented by a half mirror and two panels, only half of brightness loss is experienced compared to multiplicative LF displays with 2 layers, and no time-division is required to provide images for multi-layer displays. The images for presentation planes are processed by light field factorization and optimized with the presented algorithm. Retinal images are reconstructed based on various accommodation states and display types to check the accommodation response and utilized to compare the proposed displays with existing displays. With ray tracing method, retinal images generated by the proposed displays can be obtained. To verify the feasibility of the system, a prototype of hybrid multi-layer displays was implemented and display photographs were captured with different accommodation states of camera. With the simulation results and experimental results, this system was confirmed to support accommodation cues in a range of 1.8 diopters.


Mitochondrial energy-transducing nicotinamide nucleotide transhydrogenase. Purification and properties of the proteinase K-bisected enzyme.
The mitochondrial proton-translocating nicotinamide nucleotide transhydrogenase is embedded in the inner membrane as a homodimer of monomer Mr = 109,288. Its N-terminal 430 residues and C-terminal 200 residues protrude into the matrix, whereas its central 400 residues appear to intercalate into the inner membrane as 14 hydrophobic clusters of about 20 residues each (Yamaguchi, M., and Hatefi, Y. (1991) J. Biol. Chem. 266, 5728-5735). Treatment of mitoplasts (mitochondria denuded of outer membrane) with several proteolytic enzymes cleaves the transhydrogenase into a 72-kDa N-terminal and a 37-kDa C-terminal fragment. The cleavage site of proteinase K was determined to be Ala690-Ala691, which is located in a small loop of the transhydrogenase exposed on the cytosolic side of the inner membrane. This paper shows that the bisected transhydrogenase can be purified from proteinase K-treated mitoplasts with retention of greater than or equal to 85% transhydrogenase activity. The inactivation rate of the bisected enzyme by trypsin and N-ethylmaleimide was altered in the presence of NADP and NADPH, suggesting substrate-induced conformation changes similar to those reported previously for the intact transhydrogenase. Also, like the intact enzyme, proteoliposomes of the bisected transhydrogenase were capable of membrane potential formation and internal acidification coupled to NADPH----NAD transhydrogenation. The properties of the bisected transhydrogenase have been discussed in relation to those of the two-subunit Escherichia coli transhydrogenase, the bisected lac permease (via gene restriction), and the fragmented and reconstituted bacteriorhodopsin.


A retrospective study of the role of an occupational therapist in the cancer nutrition rehabilitation program.
The purpose of the study was to determine how frequently each domain of activity was addressed and how frequently specific interventions were used by an occupational therapist (OT) with cancer patients who attended an 8-week Cancer Nutrition and Rehabilitation (CNR) program. Sixty-two patients with cancer were assessed. All received interventions by the OT within the CNR program. The following activity domains: (1) self-care, (2) productivity, and (3) leisure that were addressed during appointments with the OT were recorded following each visit. Seven categories of interventions were predetermined and their use was recorded using a checklist. Descriptive statistics were conducted and revealed that 36% of the therapist's time was spent assessing patients' functional capacity while 64% was spent providing interventions. The OT's interventions addressed leisure and exercise (54%), productive activities such as housework and paid employment (32%), and basic activities of daily living (14%). The frequency of specific interventions provided were as follows: 40% in teaching of energy conservation and activity management techniques, 33% in goal setting/support and counseling, 9% in cognitive retraining/stimulation, 6% in communication with community agencies, and 4% in teaching of joint and bone protection techniques, help with management of neuropathies, and education on scar management respectively. It is suggested that OTs practicing in oncology use a variety of interventions to better address productive and leisure activities. The data suggests that limitations in these areas were more prevalent than in self-care activities. Further study is needed to examine OT interventions in oncology.


Terrestrial reproduction as an adaptation to steep terrain in African toads.
How evolutionary novelties evolve is a major question in evolutionary biology. It is widely accepted that changes in environmental conditions shift the position of selective optima, and advancements in phylogenetic comparative approaches allow the rigorous testing of such correlated transitions. A longstanding question in vertebrate biology has been the evolution of terrestrial life histories in amphibians and here, by investigating African bufonids, we test whether terrestrial modes of reproduction have evolved as adaptations to particular abiotic habitat parameters. We reconstruct and date the most complete species-level molecular phylogeny and estimate ancestral states for reproductive modes. By correlating continuous habitat measurements from remote sensing data and locality records with life-history transitions, we discover that terrestrial modes of reproduction, including viviparity evolved multiple times in this group, most often directly from fully aquatic modes. Terrestrial modes of reproduction are strongly correlated with steep terrain and low availability of accumulated water sources. Evolutionary transitions to terrestrial modes of reproduction occurred synchronously with or after transitions in habitat, and we, therefore, interpret terrestrial breeding as an adaptation to these abiotic conditions, rather than an exaptation that facilitated the colonization of montane habitats.