Adaptive neural control for output feedback nonlinear systems using a barrier Lyapunov function.
In this brief, adaptive neural control is presented for a class of output feedback nonlinear systems in the presence of unknown functions. The unknown functions are handled via on-line neural network (NN) control using only output measurements. A barrier Lyapunov function (BLF) is introduced to address two open and challenging problems in the neuro-control area: 1) for any initial compact set, how to determine a priori the compact superset, on which NN approximation is valid; and 2) how to ensure that the arguments of the unknown functions remain within the specified compact superset. By ensuring boundedness of the BLF, we actively constrain the argument of the unknown functions to remain within a compact superset such that the NN approximation conditions hold. The semiglobal boundedness of all closed-loop signals is ensured, and the tracking error converges to a neighborhood of zero. Simulation results demonstrate the effectiveness of the proposed approach.


Bipolar disorder and its outcomes: two cohorts, 1875-1924 and 1994-2007, compared.
We compared admission rates and outcomes for bipolar disorder patients using the medical records of patients with a first hospital admission in 1875-1924 retrospectively diagnosed based on International Classification of Diseases (ICD)-10 criteria, and patients with a first admission in 1994-2007. The incidences of first admissions in the historical and contemporary periods are comparable: 1.2 and 1.3 per hundred thousand per year, respectively. Manic episodes constituted a greater proportion of admissions historically, while depressive episodes made up more in the contemporary sample. There is no evidence for a reduction in the mean inter-admission intervals with duration of illness. This study suggests that modern treatments may have decreased lengths of stay in hospital, but at a cost of contributing to more admissions. It also points to a shift in the threshold for admissions.


Trypanosoma cruzi infection activates extracellular signal-regulated kinase in cultured endothelial and smooth muscle cells.
Trypanosoma cruzi infection causes cardiomyopathy and vasculopathy. We examined the consequence of this infection for the mitogen-activated protein kinase (MAPK) pathways, which regulate cell proliferation in cultured human umbilical vein endothelial and vascular smooth muscle cells. Infection of these cells resulted in activation of extracellular signal-regulated kinases 1and 2 (ERK1/2) but not c-Jun N-terminal kinase or p38 MAPK. Treatment of these cells with the MAPK kinase inhibitor PD98059 prior to infection blocked the increase in phosphorylated ERK1/2 seen with infection. Heat-killed parasites did not activate ERK1/2, indicating that activation of ERK1/2 was dependent on infection of these cells by live parasites. Furthermore, transfection with dominant-negative Raf(301) or Ras(N17) constructs reduced the infection-associated levels of phospho-ERK1/2, indicating that the activation of ERK1/2 involved the Ras-Raf-ERK pathway. Infection also resulted in an increase in activator protein 1 (AP-1) activity, which was inhibited by transfection with a dominant-negative Raf(301) construct. T. cruzi-infected endothelial cells secreted endothelin-1 and interleukin-1beta, which activated ERK1/2 and induced cyclin D1 expression in uninfected smooth muscle cells. These data suggest a possible molecular paradigm for the pathogenesis of the vasculopathy and the cardiovascular remodeling associated with T. cruzi infection.


A synoviocyte model for osteoarthritis and rheumatoid arthritis: response to Ibuprofen, betamethasone, and ginger extract-a cross-sectional in vitro study.
This study aimed at determining if synovial cell cultures from rheumatoid arthritis (RA), osteoarthritis (OA), and healthy controls (HC) differ and are suitable disease models in pharmacological studies, and tested their response to some anti-inflammatory drugs. Synovial cells were isolated from synovial membrane or joint fluid. Cells were cultivated and exposed to no or TNF-α stimulation without, or in the presence of, betamethasone, ibuprofen, or a standardized ginger extract. Concentrations of a panel of cytokines, growth factors, and chemokines were mapped for each culture and condition. Our cells secreted an increased amount of the cytokines IL-1β, IL-6, and IL-8 in response to TNF-α stimulation in all conditions. OA cells showed a higher IL-6 and IL-8 and a lower IL-1β production, when not stimulated, than RA and HC cells, which were similar. TNF-α stimulation caused similar IL-1β, IL-6, and IL-8 release in all groups. Ibuprofen showed no effect on cytokine production, while ginger extract was similar to betamethasone. Ginger extract was as effective an anti-inflammatory agent as betamethasone in this in vitro model. Cultured fibroblast-like synoviocytes from OA and RA subjects promise to be a useful pharmacological disease model, but further studies, to support results from such a model are needed.


A size-dependent sodium storage mechanism in Li4Ti5O12 investigated by a novel characterization technique combining in situ X-ray diffraction and chemical sodiation.
A novel characterization technique using the combination of chemical sodiation and synchrotron based in situ X-ray diffraction (XRD) has been detailed illustrated. The power of this novel technique was demonstrated in elucidating the structure evolution of Li4Ti5O12 upon sodium insertion. The sodium insertion behavior into Li4Ti5O12 is strongly size dependent. A solid solution reaction behavior in a wide range has been revealed during sodium insertion into the nanosized Li4Ti5O12 (~44 nm), which is quite different from the well-known two-phase reaction of Li4Ti5O12/Li7Ti5O12 system during lithium insertion, and also has not been fully addressed in the literature so far. On the basis of this in situ experiment, the apparent Na(+) ion diffusion coefficient (DNa+) of Li4Ti5O12 was estimated in the magnitude of 10(-16) cm(2) s(-1), close to the values estimated by electrochemical method, but 5 order of magnitudes smaller than the Li(+) ion diffusion coefficient (D(Li+) ~10(-11) cm(2) s(-1)), indicating a sluggish Na(+) ion diffusion kinetics in Li4Ti5O12 comparing with that of Li(+) ion. Nanosizing the Li4Ti5O12 will be critical to make it a suitable anode material for sodium-ion batteries. The application of this novel in situ chemical sodiation method reported in this work provides a facile way and a new opportunity for in situ structure investigations of various sodium-ion battery materials and other systems.


Regulatory Focus, Proximity to Goal Weight, and Weight Loss Maintenance.
Regulatory focus theory proposes 2 self-regulatory orientations: promotion focus - related to achieving aspirations and positive outcomes - and prevention focus - related to fulfilling responsibilities and preventing negative outcomes. The investigation examined whether regulatory focus and proximity to goal weight moderated the effectiveness of a weight-loss maintenance intervention. Participants who lost ≥10% of their weight were assigned to guided or self-directed treatments and completed regulatory focus and weight goal measures. Across treatment groups, people who were more promotion-focused had better 2-year maintenance rates (defined as regain <25%) than people who were less promotion-focused, especially if far from their goal weight (.59 versus .44). In the guided group, people who were more prevention-focused had better maintenance rates than people who were less prevention-focused if closer to their goal weight (.69 versus .42), but poorer maintenance rates if farther from their goal (.36 versus .72). In the self-directed group, prevention focus was unrelated to maintenance. Regulatory focus and proximity to goal weight moderated intervention effectiveness. Maintenance may be enhanced by tailoring treatments to regulatory focus and goal weight (eg, prevention-focused people far from their goals may need extra weight-loss support before focusing on maintenance).


Criteria for decision making after endoscopic resection of well-differentiated rectal carcinoids with regard to potential lymphatic spread.
Rectal carcinoids are low-grade malignancies that are usually treated by endoscopic resection. However, on pathologic examination, resection margins that are positive for carcinoid cells are frequently found. Patient outcomes were reviewed after endoscopic resection of rectal carcinoids and the clinical significance of possible residual disease, as defined by pathologic and endoscopic examination, was evaluated. The medical records and endoscopic findings of 347 patients presenting with rectal carcinoids to 14 university hospitals in Korea between January 1999 and June 2007 were retrospectively analyzed. A total of 304 patients were treated with endoscopic resection, and 43 patents were treated with surgery. In the endoscopic resection group, the complete resection rate was 88.2% based on endoscopic appearance (CR-E) and 60.2% based on pathologic evaluation (CR-P). The agreement between CR-E and CR-P was low (κ=0.192). No residual tumors were found in 77 of 85 patients (90.6%) who were CR-E but not CR-P and who had endoscopic biopsy taken at 24-month follow-up. The receiver-operating characteristic curve identified an optimal cut-off value of 10.5 mm, at which the sensitivity and the specificity for metastasis were 100% and 89%, respectively. The risk factors for metastasis by multivariate analysis were tumor size, increased mitotic rate, and lymphovascular invasion. Endoscopic resection is a safe and effective modality for treating well-differentiated rectal carcinoids smaller than 10 mm in diameter. Discrepancies were observed between CR-E and CR-P. The risk factors for metastasis were tumor size, increased mitotic rate, and lymphovascular invasion.


Prevalence of upper and lower gastrointestinal tract findings in liver transplant candidates undergoing screening endoscopic evaluation.
The incidence of esophageal and gastric varices and portal hypertensive gastropathy (PHG) has been well studied in cirrhotic patients. Because little is known of the prevalence of other upper and lower gastrointestinal tract pathology in pre-liver transplant candidates, we retrospectively studied the prevalence of and factors associated with these findings. One hundred and twenty pre-liver transplant candidates underwent esophagogastroduodenoscopy to evaluate for varices, and 71 of them also underwent flexible sigmoidoscopy to screen for colorectal carcinoma. The association of upper and lower GI tract pathology with Child-Pugh Class, etiology of cirrhosis, and signs of portal hypertension, including presence and size of esophageal varices, presence of gastric varices, PHG, ascites, and splenomegaly, was analyzed using univariate and multivariate analysis. Etiology of cirrhosis among 87 men and 33 women (mean age, 52 yr) included 25% hepatitis C, 27% hepatitis C/alcohol, 15% alcohol, 10% primary sclerosing cholangitis/primary biliary cirrhosis, 9% cryptogenic, 8% metabolic, and 6% hepatitis B. Prevalence of Child-Pugh Classes A, B, and C were 34%, 49%, and 17%, respectively; 73% of patients had esophageal varices (23% were large), 62% PHG (23% were severe), and 16% gastric varices. Excluding varices and PHG, endoscopic findings in the upper GI tract (n = 120) included: 13% esophagitis/ulcers, 7.5% gastritis, 8% duodenitis, 2% Barrett's esophagus, 3% duodenal ulcers, and 2% gastric ulcers. Findings in the lower gastrointestinal tract (n = 71) included 21% adenomatous polyps, 21% internal hemorrhoids, 15% diverticulosis, 7% rectal varices, 3% colopathy, and 3% vascular ectasias. Univariate analysis revealed that there was a significant association between rectal varices and severe PHG (p < 0.05). This association was not maintained when multivariate analysis was performed. Among all the findings, only rectal varices and colopathy were of higher prevalence in the pre-liver transplant population than that reported for the general population. No significant associations were found between these gastrointestinal tract lesions and patient characteristics.


Origins of knowledge.
Experiments with young infants provide evidence for early-developing capacities to represent physical objects and to reason about object motion. Early physical reasoning accords with 2 constraints at the center of mature physical conceptions: continuity and solidity. It fails to accord with 2 constraints that may be peripheral to mature conceptions: gravity and inertia. These experiments suggest that cognition develops concurrently with perception and action and that development leads to the enrichment of conceptions around an unchanging core. The experiments challenge claims that cognition develops on a foundation of perceptual or motor experience, that initial conceptions are inappropriate to the world, and that initial conceptions are abandoned or radically changed with the growth of knowledge.


The Neuronal Encoding of Oral Fat by the Coefficient of Sliding Friction in the Cerebral Cortex and Amygdala.
Fat in the diet contributes to the pleasant mouthfeel of many foods, but overconsumption may contribute to obesity. Here we analyze what properties of fat in the mouth are sensed, by analyzing the responses of neurons in the macaque insular taste cortex, and two areas to which it projects the orbitofrontal cortex where the pleasantness of fat is represented, and the amygdala. We discovered that the firing rate responses of these fat-responsive neurons are correlated with the coefficient of sliding friction (CSF) and not with viscosity which reflects food thickness. Other, not fat-sensitive, neurons encoded viscosity and not the CSF. Neuronal population analyses confirmed that fat-responsive neurons conveyed information about the CSF but not about viscosity. Conversely the viscosity-sensitive neuronal population conveyed information about viscosity but not about the CSF. This new understanding of the representation of oral fat in the cerebral cortex and amygdala opens the way for the systematic development of foods with the pleasant mouthfeel of fat, together with ideal nutritional content and has great potential to contribute to healthy eating and a healthy body weight.


Fatness, fitness, and cardiometabolic risk factors among sixth-grade youth.
Examine whether cardiometabolic risk factors are predicted by fitness or fatness among adolescents. Participants are 4955 (2614 female) sixth-grade students with complete data from 42 US middle schools. Fasting blood samples were analyzed for total cholesterol, HDL- and LDL-cholesterol, triglyceride, glucose, and insulin concentrations. Waist circumference and blood pressure were assessed. Body mass index (BMI) was categorized as normal weight, overweight, or obese as a measure of fatness. Fitness was assessed using the multistage shuttle test and was converted into gender-specific quintiles. Gender-specific regression models, adjusted for race, pubertal status, and household education, were run to identify whether BMI group predicted risk factors. Models were repeated with fitness group and both fitness and fatness groups as predictors. Means for each risk factor (except HDL, which was the reverse) were significantly higher (P < 0.0001) with increased fatness and differed across all BMI groups (P < 0.001). Waist circumference, LDL-cholesterol, triglycerides, diastolic blood pressure, and insulin were inversely associated with fitness (P < 0.001). When both fatness and fitness were included in the model, BMI was associated (P < 0.001) with almost all cardiometabolic risk factors; fitness was only associated with waist circumference (both genders), LDL-cholesterol (males), and insulin (both genders). Other associations between fitness and cardiometabolic risk factors were attenuated after adjustment for BMI group. Both fatness and fitness are associated with cardiometabolic risk factors among sixth-grade youth, but stronger associations were observed for fatness. Although maintaining high levels of fitness and preventing obesity may positively affect cardiometabolic risk factors, greater benefit may be obtained from obesity prevention.


Glucagon-like peptide-1 receptor agonists and microvascular outcomes in type 2 diabetes: A systematic review and meta-analysis.
We conducted a systematic review and meta-analysis of randomized controlled trials to assess the effect of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) on microvascular endpoints in adult patients with type 2 diabetes. We included 60 studies with 60 077 patients. GLP-1 RAs marginally reduced urinary albumin-to-creatinine ratio compared with placebo or other antidiabetic agents (weighted mean difference - 2.55 mg/g; 95% confidence interval [CI] -4.37 to -0.73 and -5.52; -10.89 to -0.16, respectively) and had no clinically relevant effect on change in estimated glomerular filtration rate. Treatment with GLP-1 RAs did not increase incidence of diabetic retinopathy, macular oedema, retinal detachment and retinal haemorrhage, irrespective of comparator. Nevertheless, incidence of vitreous haemorrhage was higher in subjects treated with GLP-1 RAs compared with placebo (odds ratios 1.93; 95% CI 1.09 to 3.42). In conclusion, GLP-1 RAs are safe regarding nephropathy- and retinopathy-related outcomes. Caution may be warranted for incidence of vitreous haemorrhage. The low overall quality of evidence highlights the need for consistent assessment and reporting of microvascular endpoints in future trials.


Effectiveness of novel, lower cost molecular human papillomavirus-based tests for cervical cancer screening in rural china.
This study examined the efficacy of the OncoE6™ Cervical Test, careHPV™ and visual inspection with acetic acid (VIA) in identifying women at risk for cervical cancer and their capability to detect incident cervical precancer and cancer at 1-year follow-up. In a population of 7,543 women living in rural China, women provided a self-collected and two clinician-collected specimens and underwent VIA. All screen positive women for any of the tests, a ∼ 10% random sample of test-negative women that underwent colposcopy at baseline, and an additional ∼ 10% random sample of test-negative women who did not undergo colposcopy at baseline (n = 3,290) were recruited. 2,904 women were rescreened 1 year later using the same tests, colposcopic referral criteria, and procedures. Sensitivities of baseline tests to detect 1-year cumulative cervical intraepithelial neoplasia Grade 3 or cancer (CIN3+) were 96.5% and 81.6% for careHPV™ on clinician-collected and self-collected specimens, respectively, and 54.4% for OncoE6™ test. The OncoE6™ test was very specific (99.1%) and had the greatest positive predictive value (PPV; 47.7%) for CIN3+. Baseline and 1-year follow-up cervical specimens testing HPV DNA positive was sensitive (88.0%) but poorly predictive (5.5-6.0%) of incident CIN2+, whereas testing repeat HPV16, 18 and 45 E6 positive identified only 24.0% of incident CIN2+ but had a predictive value of 33.3%. This study highlights the different utility of HPV DNA and E6 tests, the former as a screening and the latter as a diagnostic test, for detection of cervical precancer and cancer.


Computer-assisted initial diagnosis of rare diseases.
Introduction. Most documented rare diseases have genetic origin. Because of their low individual frequency, an initial diagnosis based on phenotypic symptoms is not always easy, as practitioners might never have been exposed to patients suffering from the relevant disease. It is thus important to develop tools that facilitate symptom-based initial diagnosis of rare diseases by clinicians. In this work we aimed at developing a computational approach to aid in that initial diagnosis. We also aimed at implementing this approach in a user friendly web prototype. We call this tool Rare Disease Discovery. Finally, we also aimed at testing the performance of the prototype. Methods. Rare Disease Discovery uses the publicly available ORPHANET data set of association between rare diseases and their symptoms to automatically predict the most likely rare diseases based on a patient's symptoms. We apply the method to retrospectively diagnose a cohort of 187 rare disease patients with confirmed diagnosis. Subsequently we test the precision, sensitivity, and global performance of the system under different scenarios by running large scale Monte Carlo simulations. All settings account for situations where absent and/or unrelated symptoms are considered in the diagnosis. Results. We find that this expert system has high diagnostic precision (≥80%) and sensitivity (≥99%), and is robust to both absent and unrelated symptoms. Discussion. The Rare Disease Discovery prediction engine appears to provide a fast and robust method for initial assisted differential diagnosis of rare diseases. We coupled this engine with a user-friendly web interface and it can be freely accessed at http://disease-discovery.udl.cat/. The code and most current database for the whole project can be downloaded from https://github.com/Wrrzag/DiseaseDiscovery/tree/no_classifiers.


Metallopolymers for advanced sustainable applications.
Since the development of metallopolymers, there has been tremendous interest in the applications of this type of materials. The interest in these materials stems from their potential use in industry as catalysts, biomedical agents in healthcare, energy storage and production as well as climate change mitigation. The past two decades have clearly shown exponential growth in the development of many new classes of metallopolymers that address these issues. Today, metallopolymers are considered to be at the forefront for discovering new and sustainable heterogeneous catalysts, therapeutics for drug-resistant diseases, energy storage and photovoltaics, molecular barometers and thermometers, as well as carbon dioxide sequesters. The focus of this review is to highlight the advances in design of metallopolymers with specific sustainable applications.


[Regional molecular genetics centers in thoracic oncology: what and who should be tested?].
Management of NSCLC patients is more and more individualized especially on the base of bioguided treatments. In order to guarantee an access for all the patients too this type of strategy, the French NCI supports since 2006 a nationwide network of 28 regional genetics center. The financial support is based on public funds. The French NCI recommends today the assessment of seven biomarkers for all stage IV non squamous NSCLC patients. Due to financial and technical reasons, this recommendation must be followed. However, the molecular profiling of lung cancer patients would ideally be extended across all stages and all histological types of the disease in order to improve our knowledge in this field and provides the patient with an opportunity to access a bioguided treatment as frequently as possible.


Comparing the predictive values of diagnostic tests: sample size and analysis for paired study designs.
Although statistical methodology is well developed for comparing diagnostic tests in terms of their sensitivities and specificities, comparative inference about predictive values is not. In this paper we consider the design and analysis of studies comparing the positive and negative predictive values of two diagnostic tests that are measured on all subjects. We focus on comparing tests using the relative positive and negative predictive values. We discuss directly estimating these quantities from the data and derive analytic variance expressions. Sample size formulas for study design ensue. We analyze data on patients with cystic fibrosis to illustrate the methodology. This approach is compared and contrasted with an existing regression framework that can also be used for similar analysis purposes and yields similar results. We have developed a new approach for comparing the predictive values of two tests that gives rise to sample size formulas for study design.


Transcriptional profiling of the spleen in progressive visceral leishmaniasis reveals mixed expression of type 1 and type 2 cytokine-responsive genes.
The Syrian golden hamster (Mesocricetus aureus) has been used as a model to study infections caused by a number of human pathogens. Studies of immunopathogenesis in hamster infection models are challenging because of the limited availability of reagents needed to define cellular and molecular determinants. We sequenced a hamster cDNA library and developed a first-generation custom cDNA microarray that included 5131 unique cDNAs enriched for immune response genes. We used this microarray to interrogate the hamster spleen response to Leishmania donovani, an intracellular protozoan that causes visceral leishmaniasis. The hamster model of visceral leishmaniasis is of particular interest because it recapitulates clinical and immunopathological features of human disease, including cachexia, massive splenomegaly, pancytopenia, immunosuppression, and ultimately death. In the microarray a differentially expressed transcript was identified as having at least a 2-fold change in expression between uninfected and infected groups and a False Discovery Rate of <5%. Following a relatively silent early phase of infection (at 7 and 14 days post-infection only 8 and 24 genes, respectively, were differentially expressed), there was dramatic upregulation of inflammatory and immune-related genes in the spleen (708 differentially expressed genes were evident at 28 days post-infection). The differentially expressed transcripts included genes involved in inflammation, immunity, and immune cell trafficking. Of particular interest there was concomitant upregulation of the IFN-γ and interleukin (IL)-4 signaling pathways, with increased expression of a battery of IFN-γ- and IL-4-responsive genes. The latter included genes characteristic of alternatively activated macrophages. Transcriptional profiling was accomplished in the Syrian golden hamster, for which a fully annotated genome is not available. In the hamster model of visceral leishmaniasis, a robust and functional IFN-γ response did not restrain parasite load and progression of disease. This supports the accumulating evidence that macrophages are ineffectively activated to kill the parasite. The concomitant expression of IL-4/IL-13 and their downstream target genes, some of which were characteristic of alternative macrophage activation, are likely to contribute to this. Further dissection of mechanisms that lead to polarization of macrophages toward a permissive state is needed to fully understand the pathogenesis of visceral leishmaniasis.


Musical training induces functional plasticity in human hippocampus.
Training can change the functional and structural organization of the brain, and animal models demonstrate that the hippocampus formation is particularly susceptible to training-related neuroplasticity. In humans, however, direct evidence for functional plasticity of the adult hippocampus induced by training is still missing. Here, we used musicians' brains as a model to test for plastic capabilities of the adult human hippocampus. By using functional magnetic resonance imaging optimized for the investigation of auditory processing, we examined brain responses induced by temporal novelty in otherwise isochronous sound patterns in musicians and musical laypersons, since the hippocampus has been suggested previously to be crucially involved in various forms of novelty detection. In the first cross-sectional experiment, we identified enhanced neural responses to temporal novelty in the anterior left hippocampus of professional musicians, pointing to expertise-related differences in hippocampal processing. In the second experiment, we evaluated neural responses to acoustic temporal novelty in a longitudinal approach to disentangle training-related changes from predispositional factors. For this purpose, we examined an independent sample of music academy students before and after two semesters of intensive aural skills training. After this training period, hippocampal responses to temporal novelty in sounds were enhanced in musical students, and statistical interaction analysis of brain activity changes over time suggests training rather than predisposition effects. Thus, our results provide direct evidence for functional changes of the adult hippocampus in humans related to musical training.


The Regret Coping Scale for Health-Care Professionals (RCS-HCP): A validation study with Danish social educators.
Coping with regret has a substantial impact on wellbeing and mental health, but has rarely been investigated in an occupational setting. To translate the Regret Coping Scale for Health-Care Professionals (RCS-HCP) and explore internal consistency, construct-, criterion- and predictive validity. The instrument was translated using forward- back method. The qualities were evaluated with a sample of 2758 social educators using exploratory and confirmatory factor analysis as well as Cronbach's alpha, Pearson correlation, and multivariable regression. The translated instrument showed a trend similar to the original instrument. A 10-item version resulted from the research being reported. The reduced RCS-HCP showed improved fit (Full model, 15 items); CFI = 0.91, TLI = 0.89, RMSEA = 0.66, PClose = 0.000 and BIC = 1392 vs. (Reduced instrument, 10 items); CFI = 0.97, TLI = 0.96, RMSEA = 0.05, PClose = 0.499 and BIC 307. This instrument had acceptable internal consistency for short scales (Cronbach's alpha = 0.65, 0.69 and 0.84 respectively). The subscales correlated as expected with measures of health and occupational factors, coefficient ranging from 0.182 to 0.399. Also, the RCS-HCP predicted stress three month later ΔF[3,2747] = 15.1, p < 0.001, but with very small effect ΔR2 = 0.01, p≤0.001. The 10-item Danish version of the RCS-HCP is a valid instrument for measuring coping with regret in health related work.


Potent and broad neutralization of HIV-1 subtype C by plasma antibodies targeting a quaternary epitope including residues in the V2 loop.
The targets of broadly cross-neutralizing (BCN) antibodies are of great interest in the HIV vaccine field. We have identified a subtype C HIV-1-superinfected individual, CAP256, with high-level BCN activity, and characterized the antibody specificity mediating breadth. CAP256 developed potent BCN activity peaking at 3 years postinfection, neutralizing 32 (76%) of 42 heterologous viruses, with titers of antibodies against some viruses exceeding 1:10,000. CAP256 showed a subtype bias, preferentially neutralizing subtype C and A viruses over subtype B viruses. CAP256 BCN serum targeted a quaternary epitope which included the V1V2 region. Further mapping identified residues F159, N160, L165, R166, D167, K169, and K171 (forming the FN/LRD-K-K motif) in the V2 region as crucial to the CAP256 epitope. However, the fine specificity of the BCN response varied over time and, while consistently dependent on R166 and K169, became gradually less dependent on D167 and K171, possibly contributing to the incremental increase in breadth over 4 years. The presence of an intact FN/LRD-K-K motif in heterologous viruses was associated with sensitivity, although the length of the adjacent V1 loop modulated the degree of sensitivity, with a shorter V1 region significantly associated with higher titers. Repair of the FN/LRD-K-K motif in resistant heterologous viruses conferred sensitivity, with titers sometimes exceeding 1:10,000. Comparison of the CAP256 epitope with that of the PG9/PG16 monoclonal antibodies suggested that these epitopes overlapped, adding to the mounting evidence that this may represent a common neutralization target that should be further investigated as a potential vaccine candidate.


Fluid Intelligence and Automatic Neural Processes in Facial Expression Perception: An Event-Related Potential Study.
The relationship between human fluid intelligence and social-emotional abilities has been a topic of considerable interest. The current study investigated whether adolescents with different intellectual levels had different automatic neural processing of facial expressions. Two groups of adolescent males were enrolled: a high IQ group and an average IQ group. Age and parental socioeconomic status were matched between the two groups. Participants counted the numbers of the central cross changes while paired facial expressions were presented bilaterally in an oddball paradigm. There were two experimental conditions: a happy condition, in which neutral expressions were standard stimuli (p = 0.8) and happy expressions were deviant stimuli (p = 0.2), and a fearful condition, in which neutral expressions were standard stimuli (p = 0.8) and fearful expressions were deviant stimuli (p = 0.2). Participants were required to concentrate on the primary task of counting the central cross changes and to ignore the expressions to ensure that facial expression processing was automatic. Event-related potentials (ERPs) were obtained during the tasks. The visual mismatch negativity (vMMN) components were analyzed to index the automatic neural processing of facial expressions. For the early vMMN (50-130 ms), the high IQ group showed more negative vMMN amplitudes than the average IQ group in the happy condition. For the late vMMN (320-450 ms), the high IQ group had greater vMMN responses than the average IQ group over frontal and occipito-temporal areas in the fearful condition, and the average IQ group evoked larger vMMN amplitudes than the high IQ group over occipito-temporal areas in the happy condition. The present study elucidated the close relationships between fluid intelligence and pre-attentive change detection on social-emotional information.


Targeted next-generation sequencing in myelodysplastic syndromes and prognostic interaction between mutations and IPSS-R.
A 27-gene panel was used for next-generation sequencing (NGS) in 179 patients (median age 73 years) with primary myelodysplastic syndromes (MDS); risk distribution according to the revised International Prognostic Scoring System (IPSS-R) was 11% very high, 18% high, 17% intermediate, 38% low and 16% very low. At least one mutation/variant was detected in 147 (82%) patients; 23% harbored three or more mutations/variants. The most frequent mutations/variants included ASXL1 (30%), TET2 (25%), SF3B1 (20%), U2AF1 (16%), SRSF2 (16%), TP53 (13%), RUNX1 (11%), and DNMT3A (10%). At a median follow up of 30 months, 148 (83%) deaths and 26 (15%) leukemic transformations were recorded. Multivariable analysis of mutations/variants identified ASXL1 (HR 1.7, 95% CI 1.2-2.5), SETBP1 (HR 4.1, 95% CI 1.6-10.2) and TP53 (HR 2.2, 95% CI 1.3-3.4) as risk factors for overall and SRSF2 (HR 3.9, 95% CI 1.5-10.2), IDH2 (HR 3.7, 95% CI 1.2-11.4), and CSF3R (HR 6.0, 95% CI 1.6-22.6) for leukemia-free survival. Addition of age to the multivariable model did not affect these results while accounting for IPSS-R weakened the significance of TP53 mutations/variants (P = .1). An apparently favorable survival impact of SF3B1 mutations was no longer evident after adjustment for IPSS-R. Approximately 41% and 20% of patients harbored at least one adverse mutation/variant for overall and leukemia-free survival, respectively. Number of mutations/variants did not provide additional prognostic value. The survival impact of adverse mutations was most evident in IPSS-R very low/low risk patients. These observations suggest that targeted NGS might assist in treatment decision-making in lower risk MDS.


Initial events during the evolution of C4 photosynthesis in C3 species of Flaveria.
The evolution of C4 photosynthesis in many taxa involves the establishment of a two-celled photorespiratory CO2 pump, termed C2 photosynthesis. How C3 species evolved C2 metabolism is critical to understanding the initial phases of C4 plant evolution. To evaluate early events in C4 evolution, we compared leaf anatomy, ultrastructure, and gas-exchange responses of closely related C3 and C2 species of Flaveria, a model genus for C4 evolution. We hypothesized that Flaveria pringlei and Flaveria robusta, two C3 species that are most closely related to the C2 Flaveria species, would show rudimentary characteristics of C2 physiology. Compared with less-related C3 species, bundle sheath (BS) cells of F. pringlei and F. robusta had more mitochondria and chloroplasts, larger mitochondria, and proportionally more of these organelles located along the inner cell periphery. These patterns were similar, although generally less in magnitude, than those observed in the C2 species Flaveria angustifolia and Flaveria sonorensis. In F. pringlei and F. robusta, the CO2 compensation point of photosynthesis was slightly lower than in the less-related C3 species, indicating an increase in photosynthetic efficiency. This could occur because of enhanced refixation of photorespired CO2 by the centripetally positioned organelles in the BS cells. If the phylogenetic positions of F. pringlei and F. robusta reflect ancestral states, these results support a hypothesis that increased numbers of centripetally located organelles initiated a metabolic scavenging of photorespired CO2 within the BS. This could have facilitated the formation of a glycine shuttle between mesophyll and BS cells that characterizes C2 photosynthesis.


Beta blockade during and after myocardial infarction: an overview of the randomized trials.
Long-term beta blockade for perhaps a year or so following discharge after an MI is now of proven value, and for many such patients mortality reductions of about 25% can be achieved. No important differences are clearly apparent among the benefits of different beta blockers, although some are more convenient than others (or have slightly fewer side effects), and it appears that those with appreciable intrinsic sympathomimetic activity may confer less benefit. If monitored, the side effects of long-term therapy are not a major problem, as when they occur they are easily reversible by changing the beta blocker or by discontinuation of treatment. By contrast, although very early IV short-term beta blockade can definitely limit infarct size, more reliable information about the effects of such treatment on mortality will not be available until a large trial (ISIS) reports later this year, with data on some thousands of patients entered within less than 4 hours of the onset of pain. Our aim has been not only to review the 65-odd randomized beta blocker trials but also to demonstrate that when many randomized trials have all applied one general approach to treatment, it is often not appropriate to base inference on individual trial results. Although there will usually be important differences from one trial to another (in eligibility, treatment, end-point assessment, and so on), physicians who wish to decide whether to adopt a particular treatment policy should try to make their decision in the light of an overview of all these related randomized trials and not just a few particular trial results. Although most trials are too small to be individually reliable, this defect of size may be rectified by an overview of many trials, as long as appropriate statistical methods are used. Fortunately, robust statistical methods exist--based on direct, unweighted summation of one O-E value from each trial--that are simple for physicians to use and understand yet provide full statistical sensitivity. These methods allow combination of information from different trials while avoiding the unjustified direct comparison of patients in one trial with patients in another. (Moreover, they can be extended of such data that there is no real need for the introduction of any more complex statistical methods that might be more difficult for physicians to trust.) Their robustness, sensitivity, and avoidance of unnecessary complexity make these particular methods an important tool in trial overviews.


Bone density, geometry, microstructure, and stiffness: Relationships between peripheral and central skeletal sites assessed by DXA, HR-pQCT, and cQCT in premenopausal women.
High-resolution peripheral quantitative computed tomography (HR-pQCT) is a new in vivo imaging technique for assessing 3D microstructure of cortical and trabecular bone at the distal radius and tibia. No studies have investigated the extent to which measurements of the peripheral skeleton by HR-pQCT reflect those of the spine and hip, where the most serious fractures occur. To address this research question, we performed dual-energy X-ray absorptiometry (DXA), central QCT (cQCT), HR-pQCT, and image-based finite-element analyses on 69 premenopausal women to evaluate relationships among cortical and trabecular bone density, geometry, microstructure, and stiffness of the lumbar spine, proximal femur, distal radius, and distal tibia. Significant correlations were found between the stiffness of the two peripheral sites (r = 0.86), two central sites (r = 0.49), and between the peripheral and central skeletal sites (r = 0.56-0.70). These associations were explained in part by significant correlations in areal bone mineral density (aBMD), volumetric bone mineral density (vBMD), and cross-sectional area (CSA) between the multiple skeletal sites. For the prediction of proximal femoral stiffness, vBMD (r = 0.75) and stiffness (r = 0.69) of the distal tibia by HR-pQCT were comparable with direct measurements of the proximal femur: aBMD of the hip by DXA (r = 0.70) and vBMD of the hip by cQCT (r = 0.64). For the prediction of vertebral stiffness, trabecular vBMD (r = 0.58) and stiffness (r = 0.70) of distal radius by HR-pQCT were comparable with direct measurements of lumbar spine: aBMD by DXA (r = 0.78) and vBMD by cQCT (r = 0.67). Our results suggest that bone density and microstructural and mechanical properties measured by HR-pQCT of the distal radius and tibia reflect the mechanical competence of the central skeleton.


Calendula officinalis: A New Natural Host of Pseudomonas viridiflava in Italy.
In November 2010, small necrotic spots surrounded by chlorotic halos, which sometimes enlarged and coalesced to form large dead areas, were observed on leaves of marigold (Calendula officinalis L.) plants grown in the Medieval Garden at the Agricultural Faculty of Perugia (central Italy). Cream-colored bacterial colonies were consistently isolated on nutrient agar (NA) from the diseased leaf tissues. Four representative selected strains, which were gram negative, fluorescent on King's medium B, and had oxidative but not fermentative metabolism, were subjected to a pathogenicity test by inoculating 1-month-old marigold plants. To prepare the inoculum, the bacterial strains were grown on NA at 27°C for 24 h, suspended in sterile deionized water, and adjusted to 1 × 106 CFU/ml. Sterile water was used for control plants. Marigold leaves were infiltrated with a glass atomizer at high pressure, and plants were kept in a growth chamber at 22 to 24°C, 70 μE·m-2·s-1 illumination and 12-h light period, and 80% relative humidity. Small, water-soaked necrotic spots were observed 10 days after inoculation, and the bacterium with the same cultural features of the original strains was reisolated from inoculated plants. For bacterial identification, the four original strains and two reisolates were subjected to LOPAT tests. They were levan negative, oxidase negative, potato rot positive, arginine dihydrolase negative, and tobacco hypersensitive response positive. These results were similar to those obtained with the type strain LMG 2352T of Pseudomonas viridiflava (Burkholder) Dowson. When 16S rDNA was amplified with the universal primers, P0 (6-27f Escherichia coli) and P6 (1515-1495r E. coli), and digested with the endonucleases, SacI and HinfI as previously reported (2), an identical restriction profile was obtained for marigold strains and reisolates and P. viridiflava strains, LMG 2352T, LMG 2353, LMG 5397, and NCPPB 1382. A completely different profile was obtained for P. syringae pv. syringae LMG 1247T. The 16S rDNA (1,364 bp) and the gyrB (570 bp) sequences of two selected marigold strains (GenBank Accession Nos. JN406504 and JN406505; JN406506 and JN406507), amplified by using universal and previously reported PCR primers (3), respectively, shared 100% sequence identity with P. viridiflava (GenBank Accession Nos. HM190229 and AY606763) for 16S rDNA and gyrB gene, respectively. On the basis of biochemical, physiological, molecular, and pathogenicity tests, it was concluded that the bacteria isolated from marigold leaves are P. viridiflava. To our knowledge, this is the first report of C. officinalis as a natural host of P. viridiflava. The plant was previously reported as a host of the bacterium by artificial inoculation (1). References: (1) J. F. Bradbury. Guide to Plant Pathogenic Bacteria. CAB International, Egham, UK, 1986. (2) A. J. González et al. Appl. Environ. Microbiol. 69:2936, 2003. (3) E. M. Goss et al. Genetics 169:21, 2005.


Participation of adult patients in healthcare.
In this study, the question of health literacy in adult patient population in the Czech Republic is explored in the context of healthcare, particularly in the South Bohemian Region. The study is based on the analysis of qualitative data which were collected during the first half of 2016. The study included 34 adult participants at the age range between 18 and 64 years. The study is focused on the involvement of adult patients in the process of decision making concerning the healthcare provided. The views of this sort of problems were recorded by the technique of semi-structured dialogues. The study results have suggested that adult individuals accept the healthcare provided by doctors or nurses prevailingly with trust. In addition, they have shown that in the sphere of health education, the adults lack the knowledge of the right for information about the individual's health condition and information about the service provided by the health insurance agency. It is regarded as desirable to deal with the topic of health literacy of adult population, particularly in the area of internet counselling and telemedicine, and to develop the space for information sharing between the doctor and nurse on one side and the patient on the other.


The safety system for the rotary blood pump, combination of the valve and LVAD pulsatile mode: in vitro test.
The significant amount of regurgitation produced by a stopped rotary blood pump is one of the major considerations for its use as an implantable left ventricular assist device (LVAD), especially if the pump accidentally stops. The installation of a valve is an option for the solution of this potential problem. However, this option may lead to thrombogenic problems, particularly if the valve motion is restricted. This in vitro study analyzes the valve performance and assesses the credibility of a rotary blood pump valve. A pulsatile pump was used as the natural heart and a centrifugal pump as the LVAD. The valve was positioned into the LVAD outflow. In the low speed range (<1,000 rpm in this test condition), normal valve motion was maintained. Also, the valve model provided a higher mean bypass flow than the model without a valve due to reduced regurgitation. However, the valve motion was drastically restricted when in the high speed range (>1,600 rpm in this condition). The pulsatile mode was applied to the LVAD by periodically changing the impeller speed (40 bpm); subsequently, a constant valve motion could be provided. A possibility exists that this pulsatile mode application could eliminate thrombosis formation around the valve. A conclusion was made that the combination of a valve and an LVAD in a pulsatile mode is considered to be a unique safety system for a rotary blood pump.


Photochemistry of free and bound Zn-chlorophyll analogues to synthetic peptides depend on the quinone and pH.
A synthetic peptide was used as a scaffold to bind Zn-Chlorophyll (ZnChl) analogues through histidine ligation to study their photochemistry in the presence of different type of quinones. The Chl analogues were chlorin e6 (Ce6), chlorin e6 trimethyl ester, pyropheophorbide a, and pheophorbide a while the quinones were PPBQ, DMBQ, NPHQ, DBTQ, DCBQ and PBQ. The binding of each ZnChl analogue to the peptide was verified by native gel electrophoresis. First the photo-stability of the ZnChl analogues were tested under continuous light. The ZnCe6 and ZnCe6TM analogues showed the least stability judged by the loss of optical signal intensity at their Qy band. The photoactivity of each ZnChl analogue was measured in the presence of each of the six quinones using time-resolved EPR spectroscopy. DMBQ was found to be the most efficient electron acceptor when all four ZnChl analogues were compared. The light-induced electron transfer between the ZnChl analogues complexed with the peptide and DMBQ were also measured using time-resolved EPR spectroscopy. The ZnCe6-peptide complex exhibited the highest photoactivity. The electron transfer in the complex was faster and the photoactivity yield was higher than those values obtained for free ZnCe6 and DMBQ. The fast phase of kinetics can be attributed to intra-protein electron transfer in the complex since it was not observed in the presence of DMBQ-glutathione adduct. Unlike free ZnCe6, the ZnCe6-peptide complex was robust and demonstrated very similar photoactivity efficiency in pH values 10, 8.0 and 5.0. The electron transfer kinetics were pH dependent and appeared to be modulated by the peptide charge and possibly fold. The charge recombination rate was slowed by an order of magnitude when the pH value was changed from 10.0 to 5.0. The implications of constructing the photoactive peptide complexes in terms of artificial photosynthesis are discussed.


Exonic versus intronic SNPs: contrasting roles in revealing the population genetic differentiation of a widespread bird species.
Recent years have seen considerable progress in applying single nucleotide polymorphisms (SNPs) to population genetics studies. However, relatively few have attempted to use them to study the genetic differentiation of wild bird populations and none have examined possible differences of exonic and intronic SNPs in these studies. Here, using 144 SNPs, we examined population genetic differentiation in the saker falcon (Falco cherrug) across Eurasia. The position of each SNP was verified using the recently sequenced saker genome with 108 SNPs positioned within the introns of 10 fragments and 36 SNPs in the exons of six genes, comprising MHC, MC1R and four others. In contrast to intronic SNPs, both Bayesian clustering and principal component analyses using exonic SNPs consistently revealed two genetic clusters, within which the least admixed individuals were found in Europe/central Asia and Qinghai (China), respectively. Pairwise D analysis for exonic SNPs showed that the two populations were significantly differentiated and between the two clusters the frequencies of five SNP markers were inferred to be influenced by selection. Central Eurasian populations clustered in as intermediate between the two main groups, consistent with their geographic position. But the westernmost populations of central Europe showed evidence of demographic isolation. Our work highlights the importance of functional exonic SNPs for studying population genetic pattern in a widespread avian species.


Combined PI3K/Akt and Smad2 Activation Promotes Corneal Endothelial Cell Proliferation.
The purpose of this study was to develop a culture method for expansion of corneal endothelial cells (CEC) based on the combined activation of PI3K/Akt and Smad2. Morphology, proliferation, and migration of cultured rabbit and nonhuman primate CEC were examined in the presence of the PI3K/Akt activators IGF-1 and heregulin beta in combination with the Smad2 activator activin A. Phenotypic characterization of CEC was performed at the RNA and protein levels. Cell pump function and transepithelial electric resistance were used for in vitro functional assessment of CEC. Finally, ex vivo-expanded rabbit CEC were transplanted into a model of endothelial damage in rabbit corneas. Treatment of rabbit and nonhuman primate CEC in vitro with IGF-1, heregulin beta, and activin A induced an upregulation of PI3K/Akt and Smad2 signaling pathways and an increase in proliferation and migration of CEC expressing ZO-1, connexin-43, and Na+/K+-ATPase. Cell pump function evaluation revealed the complete functionality of cultured CEC. Injection of rabbit CEC successfully produced recovery of normal corneal thickness in a rabbit model of endothelial dysfunction. We demonstrated that the combined activation of PI3K/Akt and Smad2 results in in vitro expansion of phenotypic and functional CEC. Expanded cells were able to contribute to restoration of corneal endothelium in a rabbit model. These findings may represent a new therapeutic approach for treating corneal endothelial diseases.


SHBG, Sex Steroids, and Kyphosis in Older Men: The MrOS Study.
Accentuated kyphosis is associated with adverse health outcomes, including falls and fractures. Low bone density is a risk factor for hyperkyphosis, and each vertebral fracture adds roughly 4° to forward spine curvature. Sex steroids, in particular low bioavailable estradiol and high sex hormone-binding globulin (SHBG), are associated with bone loss and high SHBG is associated with vertebral fractures in older men. We, therefore, hypothesized that low bioavailable estradiol and high SHBG would be associated with worse kyphosis. To test this hypothesis, we examined the cross-sectional associations between individual bioavailable sex hormones and SHBG with radiographically assessed kyphosis. Participants included 1500 men aged 65 and older from the Osteoporotic Fractures in Men (MrOS) Study, in whom baseline measures of kyphosis and sex hormones were available. Modified Cobb angle of kyphosis, calculated from T4 through T12, was assessed from supine lateral spine radiographs. Serum total estradiol and total testosterone were measured by mass spectrometry, and bioavailable sex steroids were calculated from mass action equations. After adjustment for age and other confounding variables, no association was found between bioavailable estradiol or testosterone and Cobb angle, either when kyphosis was analyzed as a continuous variable or dichotomized into highest versus lower three quartiles. In linear regression models adjusted for age and clinic site, there was a significant association between SHBG and kyphosis (parameter estimate = 0.76 per SD increase, p = 0.01). In the fully adjusted model, this association was weakened and of only borderline statistical significance (parameter estimate = 0.61 per SD, p = 0.05). Logistic models demonstrated similar findings. Although associated with bone loss, we did not demonstrate that low bioavailable estradiol translates into worse kyphosis in older men. High SHBG is associated with bone loss and vertebral fractures. Our results suggest that high SHBG may also be a risk factor for hyperkyphosis. © 2016 American Society for Bone and Mineral Research.


An 88 fs fiber soliton laser using a quantum well saturable absorber with an ultrafast intersubband transition.
We demonstrate a 1.5 microm passively mode-locked fiber laser using an intersubband transition (ISBT) in a quantum well as a saturable absorber. The saturable absorption characteristic of faster than 1 ps in the ISBT was utilized for femtosecond pulse generation. We designed the laser cavity as a soliton laser, which enabled us to generate a stable pulse. As a result, an 88 fs, 42 MHz soliton pulse was successfully generated.


Lake eutrophication and its implications for organic carbon sequestration in Europe.
The eutrophication of lowland lakes in Europe by excess nitrogen (N) and phosphorus (P) is severe because of the long history of land-cover change and agricultural intensification. The ecological and socio-economic effects of eutrophication are well understood but its effect on organic carbon (OC) sequestration by lakes and its change overtime has not been determined. Here, we compile data from ~90 culturally impacted European lakes [~60% are eutrophic, Total P (TP) >30 μg P l(-1) ] and determine the extent to which OC burial rates have increased over the past 100-150 years. The average focussing corrected, OC accumulation rate (C ARFC ) for the period 1950-1990 was ~60 g C m(-2) yr(-1) , and for lakes with >100 μg TP l(-1) the average was ~100 g C m(-2) yr(-1) . The ratio of post-1950 to 1900-1950 C AR is low (~1.5) indicating that C accumulation rates have been high throughout the 20th century. Compared to background estimates of OC burial (~5-10 g C m(-2) yr(-1) ), contemporary rates have increased by at least four to fivefold. The statistical relationship between C ARFC and TP derived from this study (r(2) = 0.5) can be used to estimate OC burial at sites lacking estimates of sediment C-burial. The implications of eutrophication, diagenesis, lake morphometry and sediment focussing as controls of OC burial rates are considered. A conservative interpretation of the results of the this study suggests that lowland European meso- to eutrophic lakes with >30 μg TP l(-1) had OC burial rates in excess of 50 g C m(-2) yr(-1) over the past century, indicating that previous estimates of regional lake OC burial have seriously underestimated their contribution to European carbon sequestration. Enhanced OC burial by lakes is one positive side-effect of the otherwise negative impact of the anthropogenic disruption of nutrient cycles.


Human lung tumor-associated antigen identified as an extracellular matrix adhesion molecule.
A single chain glycoprotein with an estimated molecular mass of 160 kD (gp160) was previously identified as a human lung tumor-associated antigen. This tumor marker is shown here to be associated noncovalently with a second 130-kD protein. Sequential immunoprecipitation studies of surface iodinated lung tumor cell lysates reveal that this heterodimeric complex is indistinguishable serologically and structurally from the integrin VLA-2, found originally on activated T lymphocytes and platelets. The VLA-2-like complex expressed on the lung tumors possesses similar characteristic Mg2+ dependent binding of collagen and laminin as observed with VLA-2 on normal cells. RNA analysis indicates that human lung tumors express at least 20 times more VLA-2 alpha chain message than normal adult human lung tissue. The results presented here raise the possibility that the overproduction of VLA-2 may be involved in the pathogenesis of human lung tumors by modulating the invasive and metastatic potential of the tumor.


Inductive specification and axonal orientation of spinal neurons mediated by divergent bone morphogenetic protein signaling pathways.
Bone morphogenetic protein (BMP)7 evokes both inductive and axon orienting responses in dorsal interneurons (dI neurons) in the developing spinal cord. These events occur sequentially during the development of spinal neurons but in these and other cell types such inductive and acute chemotactic responses occur concurrently, highlighting the requirement for divergent intracellular signaling. Both type I and type II BMP receptor subtypes have been implicated selectively in orienting responses but it remains unclear how, in a given cell, divergence occurs. We have examined the mechanisms by which disparate BMP7 activities are generated in dorsal spinal neurons. We show that widely different threshold concentrations of BMP7 are required to elicit the divergent inductive and axon orienting responses. Type I BMP receptor kinase activity is required for activation of pSmad signaling and induction of dI character by BMP7, a high threshold response. In contrast, neither type I BMP receptor kinase activity nor Smad1/5/8 phosphorylation is involved in the low threshold orienting responses of dI axons to BMP7. Instead, BMP7-evoked axonal repulsion and growth cone collapse are dependent on phosphoinositide-3-kinase (PI3K) activation, plausibly through type II receptor signaling. BMP7 stimulates PI3K-dependent signaling in dI neurons. BMP6, which evokes neural induction but does not have orienting activity, activates Smad signaling but does not stimulate PI3K. Divergent signaling through pSmad-dependent and PI3K-dependent (Smad-independent) mechanisms mediates the inductive and orienting responses of dI neurons to BMP7. A model is proposed whereby selective engagement of BMP receptor subunits underlies choice of signaling pathway.


Characterization of the uncertainty of divergence time estimation under relaxed molecular clock models using multiple loci.
Genetic sequence data provide information about the distances between species or branch lengths in a phylogeny, but not about the absolute divergence times or the evolutionary rates directly. Bayesian methods for dating species divergences estimate times and rates by assigning priors on them. In particular, the prior on times (node ages on the phylogeny) incorporates information in the fossil record to calibrate the molecular tree. Because times and rates are confounded, our posterior time estimates will not approach point values even if an infinite amount of sequence data are used in the analysis. In a previous study we developed a finite-sites theory to characterize the uncertainty in Bayesian divergence time estimation in analysis of large but finite sequence data sets under a strict molecular clock. As most modern clock dating analyses use more than one locus and are conducted under relaxed clock models, here we extend the theory to the case of relaxed clock analysis of data from multiple loci (site partitions). Uncertainty in posterior time estimates is partitioned into three sources: Sampling errors in the estimates of branch lengths in the tree for each locus due to limited sequence length, variation of substitution rates among lineages and among loci, and uncertainty in fossil calibrations. Using a simple but analogous estimation problem involving the multivariate normal distribution, we predict that as the number of loci ([Formula: see text]) goes to infinity, the variance in posterior time estimates decreases and approaches the infinite-data limit at the rate of 1/[Formula: see text], and the limit is independent of the number of sites in the sequence alignment. We then confirmed the predictions by using computer simulation on phylogenies of two or three species, and by analyzing a real genomic data set for six primate species. Our results suggest that with the fossil calibrations fixed, analyzing multiple loci or site partitions is the most effective way for improving the precision of posterior time estimation. However, even if a huge amount of sequence data is analyzed, considerable uncertainty will persist in time estimates.


Spatial selectivity of rat hippocampal neurons: dependence on preparedness for movement.
The mammalian hippocampal formation appears to play a major role in the generation of internal representations of spatial relationships. In rats, this role is reflected in the spatially selective discharge of hippocampal pyramidal cells. The principal metric for coding spatial relationships might be the organism's own movements in space, that is, the spatial relationship between two locations is coded in terms of the movements executed in getting from one to the other. Thus, information from the motor programming systems (or "motor set") may contribute to coding of spatial location by hippocampal neurons. Spatially selective discharge of hippocampal neurons was abolished under conditions of restraint in which the animal had learned that locomotion was impossible. Therefore, hippocampal neuronal activity may reflect the association of movements with their spatial consequences.


Adherence to aerobic and muscle-strengthening components of the physical activity guidelines and mental health.
Despite a clear distinction between aerobic and muscle strengthening (MS) components in the physical activity guidelines, public health surveillance has largely focused only on aerobic components, limiting the reach of epidemiological research on the physical activity guidelines. Hence, this study investigated the association between adherence to both components (i.e. aerobic and muscle-strengthening) of the World Health Organization's physical activity guidelines and mental health among the college student population. A cross-sectional study was conducted among a nationally representative sample of Irish college students (7088 participants, M age: 23.17 years; 50.9% female). Participants were categorized as meeting both components of the guidelines (n = 41%), only the aerobic component (n = 25.3%) or the MS component (n = 7.3%), and neither (n = 26.4%). Group membership effects on mental health was determined through mixed univariate ANOVAs, with a Bonferroni correction for post hoc analyses to assess multiple comparisons. Results revealed that meeting both components of the guidelines was significantly (all p < 0.01) associated with greater self-reported happiness, body image and general health, and less mental ill-being, relative to all other respective groupings. Meeting aerobic or MS components in isolation was significantly (p < 0.05) associated with better happiness, general health and body image compared to not meeting either component. To conclude, 59% of the college-aged population are insufficiently active, and adherence to both guideline components is positively associated with mental health. Co-produced, evidence-based, physical activity interventions are needed in students and could contribute to mental health promotion.


WE-E-213CD-01: Best in Physics (Joint Imaging-Therapy) - Evaluation of Deformation Algorithm Accuracy with a Two-Dimensional Anatomical Pelvic Phantom.
To objectively evaluate the accuracy of 11 different deformable registration techniques for bladder filling. The phantom represents an axial plane of the pelvic anatomy. Urethane plastic serves as the bony anatomy and urethane rubber with three levels of Hounsfield units (HU) is used to represent fat and organs, including the prostate. A plastic insert is placed into the phantom to simulate bladder filling. Nonradiopaque markers reside on the phantom surface. Optical camera images of these markers are used to measure the positions and determine the deformation from the bladder insert. Eleven different deformable registration techniques are applied to the full- and empty-bladder computed tomography images of the phantom to calculate the deformation. The applied algorithms include those from MIMVista Software and Velocity Medical Solutions and 9 different implementations from the Deformable Image Registration and Adaptive Radiotherapy Toolbox for Matlab. The distance to agreement between the measured and calculated deformations is used to evaluate algorithm error. Deformable registration warps one image to make it similar to another. The root-mean-square (RMS) difference between the HUs at the marker locations on the empty-bladder phantom and those at the calculated marker locations on the full-bladder phantom is used as a metric for image similarity. The percentage of the markers with an error larger than 3 mm ranges from 3.1% to 28.2% with the different registration techniques. This range is 1.1% to 3.7% for a 7 mm error. The least accurate algorithm at 3 mm is also the most accurate at 7 mm. Also, the least accurate algorithm at 7 mm produces the lowest RMS difference. Different deformation algorithms generate very different results and the outcome of any one algorithm can be misleading. Thus, these algorithms require quality assurance. The two-dimensional phantom is an objective tool for this purpose.


Upper and Lower Gastrointestinal Endoscopic Findings in HIV-Infected Patients in the Era of Highly Active Antiretroviral Therapy.
Endoscopic evaluation with biopsies are instrumental in the diagnosis and management of gastrointestinal (GI) disorders in the setting of human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS), especially in the era of highly active antiretroviral therapy (HAART). A retrospective chart review of 304 HIV-positive and 199 HIV-negative patients who had undergone upper and/or lower endoscopy in an urban community hospital from the years 2012 - 2017 was performed. Inclusion criteria included men and women between the ages of 45 to 75 years, which had undergone colonoscopies between within 2012 - 2017 and had tested positive for HIV. They were selected from that population if they had complete charts that included information regarding symptoms, viral load, cluster of differentiation 4 (CD4) count, prescribed HAART medication, findings from the upper and lower colonoscopy both from the gastroenterologist's report and pathologist's report. Only then would they be added to the pool of final selection that we could compute data from and draw conclusions. Among HIV patients, those with less than 200 CD4 cells/µL counts had lower rates of diverticulosis and hemorrhoids, as compared with those with greater than 200 cells/µL counts. Other gross and histological findings (from either upper or lower endoscopy) were not statistically different between these two groups. In HIV-positive patients, gastritis, Helicobacter pylori (HP) infection, and esophagitis were significantly less common, while Candida esophagitis was more common. Among HIV patients taking different HAART regimens, the prevalence of peptic ulcers was significantly higher in those taking IIs than that in those who were not. Physicians should consider the possibility that the GI symptoms in HIV-infected patients on HAART may be due to an opportunistic infection, even when the CD4 count is more than 200 cells/µL and the viral load is low.


Evidence based medicine in clinical practice: how to advise patients on the influence of age on the outcome of surgical anterior cruciate ligament reconstruction: a review of the literature.
To determine, using a literature search, whether patient age influences the outcome of surgical reconstruction of a torn anterior cruciate ligament. Medline (1966 to present) was searched using the PubMed interface, Embase (1974 to present) using the Datastar system, and the Cochrane Library at the Update Software web site. Papers retrieved from the three databases were independently assessed by two reviewers using preliminary inclusion criteria. Reference lists of papers satisfying the preliminary criteria were then scanned and appropriate papers reviewed. Any new papers in turn had their reference lists scanned, this process continuing until no new papers were identified. Final inclusion criteria were then applied to all papers satisfying the preliminary inclusion criteria. The initial search identified 661 papers. Exclusion of duplicates produced 536 unique papers. Medline contained 445, Embase 185, and the Cochrane Library 31. Of the 536, 523 were assessed by abstract and 12 by full text; one paper was not retrieved. Application of the preliminary inclusion criteria produced 33 papers. Their reference lists contained 950 references. Scanning of these added six new papers to the dataset. These six had their reference lists assessed; no new papers were identified. Four of the 39 papers in the completed dataset satisfied the final inclusion criteria. There was wide variation in the total number of subjects in the four studies, ranging from 22 to 203 patients. The total number of different outcome measures was 17; only one measure was used by all four studies. None of the objective outcome measures showed any significant difference between age groups, and the subjective measures, which did show differences, were contradictory. A total of 108 interlibrary loans were requested, by a full time researcher, at a total cost of 432.00 Irish pounds over a 10 week period. When advising patients on the outcome of anterior cruciate ligament reconstruction, age should not be considered in isolation. In the absence of relevant guidelines, meta-analyses, or systematic reviews, the application of evidence based medicine to clinical practice has significant resource implications.


The pattern of pediatric respiratory illnesses admitted in ebonyi state university teaching hospital South-East Nigeria.
Reports from the developed nations reveal respiratory tract infections as the leading cause of childhood hospital admissions. Children may be admitted for a variety of respiratory illnesses. Data on the spectrum of pediatric respiratory illnesses admitted in the hospital is scarce. To determine the pattern of pediatrics respiratory illness admissions, seasonal frequency, underlying risk factors and outcome. A retrospective assessment of respiratory cases admitted in the pediatric ward from 2005 to 2010 was conducted using case notes. Parameters considered included month of presentation, age, sex, immunization and nutritional status, tools of diagnosis and patient outcome. Results were analyzed using the Statistical Package for the Social Sciences with the level of significance P ≤ 0.05. Of the 239 cases admitted, there were more males than females (1.4:1). The commonest case was Bronchopneumonia, 71.6% (171/239 out of which 161 were uncomplicated, 5 had effusions and 6 were associated with measles). Other cases were Pulmonary Tuberculosis, 10.9% (26/239), Lobar pneumonia 8.8% (21/239), Bronchiolitis, 5% (12/239), Aspiration pneumonitis 2.1% (5/239) and Bronchial asthma, 0.8% (2/239). Mortality was 7.5% (18/239) mostly from Bronchopneumonia amongst the 1-5 years old. Mortality was significantly associated with malnutrition (P < 0.001) and poor immunization status (P < 0.01). Bronchopneumonia was found to be the commonest illness with significant mortality and peak occurrence in the rainy season. More emphasis must be laid on anticipatory guidance and prevention by encouraging the immunization, good nutrition and increased attention on children even after 1 year of age.


Frogs flee from the sound of fire.
Fire has an important role in the sensory ecology of many animals. Using acoustic cues to detect approaching fires may give slow-moving animals a head start when fleeing from fires. We report that aestivating juvenile reed frogs (Hyperolius nitidulus) respond to playbacks of the sound of fire by fleeing in the direction of protective cover, where they are safe. This is a novel response to fire not known to occur in other animals. Moreover, we identify the rapid rise-time of the crackling sound of fire as the probable cue used. These results suggest that amphibian hearing not only has evolved through sexual selection, but also must be viewed in a broader context.


The reliability and validity of the Test of Adaptive Behavior in Schizophrenia (TABS).
Performance-based tests of functional capacity are important to utilize in schizophrenia where global measures may underestimate community functioning in the context of impoverished environments and disincentives to return to work. The Test of Adaptive Behavior in Schizophrenia (TABS) is a performance-based measure of adaptive functioning designed to address limitations of other available measures including limited assessment of the ability to initiate and of the ability to identify problems that occur in the course of performing functional activities. The TABS and a variety of symptom, functional outcome, and cognitive measures were administered to 264 outpatients with schizophrenia/schizoaffective disorders at an initial assessment. At 3 months, 110 subjects received a follow-up assessment. Results indicated that the TABS had very good test-retest reliability (0.80) and inter-item consistency (0.84). Moreover, TABS scores were moderately to strongly correlated with other measures of functional outcome, negative symptoms and neuropsychological test scores (convergent validity). Measures of positive symptoms were not found to be related to TABS performance (discriminate validity). The data provide preliminary evidence for the reliability and validity of the TABS. Further studies of the psychometric properties of the TABS including those examining the sensitivity of the TABS to treatments with different pharmacological agents or psychosocial treatments are encouraged.


Local and global measures of shape dynamics.
The shape and motion of cells can yield significant insights into the internal operation of a cell. We present a simple, yet versatile, framework that provides multiple metrics of cell shape and cell shape dynamics. Analysis of migrating Dictyostelium discoideum cells shows that global and local metrics highlight distinct cellular processes. For example, a global measure of shape shows rhythmic oscillations suggestive of contractions, whereas a local measure of shape shows wave-like dynamics indicative of protrusions. From a local measure of dynamic shape, or boundary motion, we extract the times and locations of protrusions and retractions. We find that protrusions zigzag, while retractions remain roughly stationary along the boundary. We do not observe any temporal relationship between protrusions and retractions. Our analysis framework also provides metrics of the boundary as whole. For example, as the cell speed increases, we find that the cell shape becomes more elongated. We also observe that while extensions and retractions have similar areas, their shapes differ.


Connectionist modeling of developmental changes in infancy: approaches, challenges, and contributions.
Connectionist models have been applied to many phenomena in infant development including perseveration, language learning, categorization, and causal perception. In this article, we discuss the benefits of connectionist networks for the advancement of theories of early development. In particular, connectionist models contribute novel testable predictions, instantiate the theorized mechanism of change, and create a unifying framework for understanding infant learning and development. We relate these benefits to the 2 primary approaches used in connectionist models of infant development. The first approach employs changes in neural processing as the basis for developmental changes, and the second employs changes in infants' experiences. The review sheds light on the unique hurdles faced by each approach as well as the challenges and solutions related to both, particularly with respect to the identification of critical model components, parameter specification, availability of empirical data, and model comparison. Finally, we discuss the future of modeling work as it relates to the study of development. We propose that connectionist networks stand to make a powerful contribution to the generation and revision of theories of early child development. Furthermore, insights from connectionist models of early development can improve the understanding of developmental changes throughout the life span.


Avian cholera in eider ducks in Maine.
Outbreaks of avian cholera (Pasteurella multocida) occur frequently in common eiders (Somateria mollissima dresseri) in Maine during early summer. Studies over a seven year period show that over 90% of the loss occurred in incubating females and might be associated with their weakened condition because females do not feed during the incubation period. High nesting densities also may contribute to the losses. The exact source of P. multocida is unknown although carrier birds were found.


Medium-term effects of SARS-CoV-2 infection on multiple vital organs, exercise capacity, cognition, quality of life and mental health, post-hospital discharge.
The medium-term effects of Coronavirus disease (COVID-19) on organ health, exercise capacity, cognition, quality of life and mental health are poorly understood. Fifty-eight COVID-19 patients post-hospital discharge and 30 age, sex, body mass index comorbidity-matched controls were enrolled for multiorgan (brain, lungs, heart, liver and kidneys) magnetic resonance imaging (MRI), spirometry, six-minute walk test, cardiopulmonary exercise test (CPET), quality of life, cognitive and mental health assessments. At 2-3 months from disease-onset, 64% of patients experienced breathlessness and 55% reported fatigue. On MRI, abnormalities were seen in lungs (60%), heart (26%), liver (10%) and kidneys (29%). Patients exhibited changes in the thalamus, posterior thalamic radiations and sagittal stratum on brain MRI and demonstrated impaired cognitive performance, specifically in the executive and visuospatial domains. Exercise tolerance (maximal oxygen consumption and ventilatory efficiency on CPET) and six-minute walk distance were significantly reduced. The extent of extra-pulmonary MRI abnormalities and exercise intolerance correlated with serum markers of inflammation and acute illness severity. Patients had a higher burden of self-reported symptoms of depression and experienced significant impairment in all domains of quality of life compared to controls (p<0.0001 to 0.044). A significant proportion of patients discharged from hospital reported symptoms of breathlessness, fatigue, depression and had limited exercise capacity. Persistent lung and extra-pulmonary organ MRI findings are common in patients and linked to inflammation and severity of acute illness. NIHR Oxford and Oxford Health Biomedical Research Centres, British Heart Foundation Centre for Research Excellence, UKRI, Wellcome Trust, British Heart Foundation.


Evaluation of movement behaviors to inform toxic baiting strategies for invasive wild pigs (Sus scrofa).
Invasive wild pigs damage agriculture, property, and natural ecosystems. To curtail damage, an effective and humane toxic bait containing microencapsulated sodium nitrite is under development. Strategies for delivering the toxic bait are needed to establish adequate spacing of bait sites, and for simultaneously accustoming wild pigs to the novel bait and wild pig-specific bait stations designed to exclude non-target species. We monitored movements of 32 Global Positioning System (GPS)-collared wild pigs relative to 41 bait sites containing placebo bait. Among the bait sites, we compared three experimental baiting strategies (and a control) to evaluate which strategy led to the most wild pigs accessing the placebo bait inside bait stations. We found that bait sites should be spaced 0.5-1 km apart to maximize opportunities for all wild pigs to find and utilize the bait sites. Baiting strategies that allowed ≥ 15 days for accustoming wild pigs to bait stations were most effective and resulted in nearly 90% of wild pigs accessing the placebo bait inside the bait stations. Bait stations excluded all non-target animals, except one instance with a raccoon (Procyon lotor). These results demonstrate the potential for toxic bait to be an effective tool for reducing populations of wild pigs with minimal risks to non-target species, if optimized delivery procedures are followed. © 2018 Society of Chemical Industry.


The effect of metal primer application and Nd:YAG laser irradiation on the shear-bond strength between polymethyl methacrylate and cobalt-chromium alloy.
The purpose of this study was to compare the shear-bond strengths (SBSs) of an acrylic resin and a cobalt-chromium (Co-Cr) alloy after applying a metal primer, Nd:YAG laser irradiation, or both to the sandblasted surface of the Co-Cr alloy. The serviceability of a removable partial denture (RPD) is dependent on the bond strength at the resin-alloy interface. No previously published studies exist on the use of Nd:YAG lasers for preparing the surface of a Co-Cr alloy in an RPD to obtain a high-strength bond between PMMA and the alloy. One-hundred twenty Co-Cr alloy specimens were sandblasted and randomly assigned to four equal groups: Group I, sandblasting; Group II, sandblasting + metal primer; Group III, sandblasting + Nd:YAG laser; and Group IV, sandblasting + Nd:YAG laser + metal primer. To establish the most appropriate fluence for modifying the surface of the sandblasted cast specimens, we conducted a preliminary study. Nd:YAG laser irradiation at a fluence of 46.9 J/cm(2) was selected. After the various surface treatments, each alloy specimen was embedded in PMMA to determine the SBS between PMMA and the alloy. Group II and III specimens exhibited higher SBSs than did those of the Group I specimens (p < 0.05), and Group IV specimens showed higher SBSs than did those of the Group II and III specimens (p < 0.05). A significant difference existed in failure types among groups (p < 0.05). Failure type was predominantly adhesive for groups I and III, but predominantly mixed for groups II and IV. Nd:YAG laser irradiation at a fluence of 46.9 J/cm(2) roughens the sandblasted surface of a Co-Cr alloy and increases the strength of the bond between PMMA and the alloy. This bond strength can be increased further by applying a metal primer to the laser-irradiated surface.


Comparison of the psychophysical properties of various intraoral film and digital systems by means of the perceptibility curve test.
To compare psychophysical properties of two intraoral films and three digital systems using the perceptibility curve (PC) test. A test object was used to determine the exposures and exposure differences between the total thickness of the test object and details consisting of holes of increasing depth. The PCs for the two intraoral films, UltraSpeed and EktaSpeed Plus, were constructed employing exposure and exposure differences from dose response functions. Integrals of the PCs were calculated to obtain the psychophysical properties of the two films. Psychophysical properties of the two films were compared with those of the three digital systems published previously (CDR, Dixel and Digora). The PC for the EktaSpeed Plus showed a slightly higher peak than that for the UltraSpeed. Available exposure ranges were comparable. The PC for the EktaSpeed Plus was shifted to the left of the exposure axis indicating its higher sensitivity as compared with UltraSpeed. All three digital systems had narrower but higher peaks compared with the films. The integrals for the digital systems were considerably larger than those for the two film types. All the three digital systems have superior psychophysical properties compared with the two tested films.


The potential for dispersal of microalgal resting cysts by migratory birds.
Most microalgal species are geographically widespread, but little is known about how they are dispersed. One potential mechanism for long-distance dispersal is through birds, which may transport cells internally (endozoochory) and deposit them during, or in-between, their migratory stopovers. We hypothesize that dinoflagellates, in particular resting stages, can tolerate bird digestion; that bird temperature, acidity, and retention time negatively affect dinoflagellate viability; and that recovered cysts can germinate after passage through the birds' gut, contributing to species-specific dispersal of the dinoflagellates across scales. Tolerance of two dinoflagellate species (Peridiniopsis borgei, a warm-water species and Apocalathium malmogiense, a cold-water species) to Mallard gut passage was investigated using in vitro experiments simulating the gizzard and caeca conditions. The effect of in vitro digestion and retention time on cell integrity, cell viability, and germination capacity of the dinoflagellate species was examined targeting both their vegetative and resting stages. Resting stages (cysts) of both species were able to survive simulated bird gut passage, even if their survival rate and germination were negatively affected by exposure to acidic condition and bird internal temperature. Cysts of A. malmogiense were more sensitive than P. borgei to treatments and to the presence of digestive enzymes. Vegetative cells did not survive conditions of bird internal temperature and formed pellicle cysts when exposed to gizzard-like acid conditions. We show that dinoflagellate resting cysts serve as dispersal propagules through migratory birds. Assuming a retention time of viable cysts of 2-12 h to duck stomach conditions, cysts could be dispersed 150-800 km and beyond.


Utilizing de Bruijn graph of metagenome assembly for metatranscriptome analysis.
Metagenomics research has accelerated the studies of microbial organisms, providing insights into the composition and potential functionality of various microbial communities. Metatranscriptomics (studies of the transcripts from a mixture of microbial species) and other meta-omics approaches hold even greater promise for providing additional insights into functional and regulatory characteristics of the microbial communities. Current metatranscriptomics projects are often carried out without matched metagenomic datasets (of the same microbial communities). For the projects that produce both metatranscriptomic and metagenomic datasets, their analyses are often not integrated. Metagenome assemblies are far from perfect, partially explaining why metagenome assemblies are not used for the analysis of metatranscriptomic datasets. Here, we report a reads mapping algorithm for mapping of short reads onto a de Bruijn graph of assemblies. A hash table of junction k-mers (k-mers spanning branching structures in the de Bruijn graph) is used to facilitate fast mapping of reads to the graph. We developed an application of this mapping algorithm: a reference-based approach to metatranscriptome assembly using graphs of metagenome assembly as the reference. Our results show that this new approach (called TAG) helps to assemble substantially more transcripts that otherwise would have been missed or truncated because of the fragmented nature of the reference metagenome. TAG was implemented in C++ and has been tested extensively on the Linux platform. It is available for download as open source at http://omics.informatics.indiana.edu/TAG CONTACT: email@example.com.


Prednisone for chronic active liver disease: dose titration, standard dose, and combination with azathioprine compared.
Among 120 consecutive patients with chronic active liver disease (CALD) randomized to different treatments, those receiving maintenance doses of prednisone 20 mg daily (Pred), prednisone in doses given on alternate days and titrated to secure resolution of clinical and biochemical abnormalities (Pred-Titrad), or a combination of prednisone 10 mg and azathioprine 50 mg daily (Comb) survived and underwent resolution of clinical and biochemical features of disease more often than a control group receiving placebo or azathioprine 100 mg daily. Histological remission occurred significantly more often with Pred and Comb than with other regimens. Major side-effects of therapy were commoner with Pred than with Comb or Pred-Titrad, which did not differ. We conclude that Comb is the initial treatment of choice for CALD, since clinical, biochemical, and histological resolution of disease activity occurs as often as with Pred, whereas early side-effects are significantly less frequent.


KRT12 mutations and in vivo confocal microscopy in two Japanese families with Meesmann corneal dystrophy.
To identify genetic mutations and study the corneal epithelium in Japanese patients with Meesmann corneal dystrophy. Laboratory investigation and prospective observational case series. Slit-lamp biomicroscopy with fluorescein vital staining and in vivo confocal microscopy were performed. Mutation screening of the KRT3 and KRT12 genes was performed via polymerase chain reaction and direct sequencing for 5 patients in 2 families. Slit-lamp biomicroscopy revealed multiple corneal intraepithelial microcysts in all patients. A clear zone was seen in the younger generation, whereas mild subepithelial opacity was seen in the older generation. In the in vivo confocal microscopy, numerous corneal intraepithelial microcysts and hyperreflective materials, which were believed to be degenerative cells, were detected closer to the basal layer of the corneal epithelium in older patients. The superficial layer contained more enlarged microcysts, and the hyperreflective materials showed atrophic changes, as compared to the basal layer. The demarcation line between the microcysts and normal epithelial cells was clearly visualized by in vivo confocal microscopy and corresponded to the demarcation line of the clear zone observed by the slit-lamp examination. Two heterozygous mutations (Q130P, L140Q) in the KRT12 gene, one of which (L140Q) was novel, were identified only in the affected patients of the families. We identified a novel missense mutation of the KRT12 gene in Meesmann corneal dystrophy. The in vivo confocal microscopy examinations revealed previously unreported depth-dependent ultrastructural changes in the living cornea of Meesmann corneal dystrophy patients.


Temperature profiles of different cooling methods in porcine pancreas procurement.
Porcine islet xenotransplantation is a promising alternative to human islet allotransplantation. Porcine pancreas cooling needs to be optimized to reduce the warm ischemia time (WIT) following donation after cardiac death, which is associated with poorer islet isolation outcomes. This study examines the effect of four different cooling Methods on core porcine pancreas temperature (n = 24) and histopathology (n = 16). All Methods involved surface cooling with crushed ice and chilled irrigation. Method A, which is the standard for porcine pancreas procurement, used only surface cooling. Method B involved an intravascular flush with cold solution through the pancreas arterial system. Method C involved an intraductal infusion with cold solution through the major pancreatic duct, and Method D combined all three cooling Methods. Surface cooling alone (Method A) gradually decreased core pancreas temperature to <10 °C after 30 min. Using an intravascular flush (Method B) improved cooling during the entire duration of procurement, but incorporating an intraductal infusion (Method C) rapidly reduced core temperature 15-20 °C within the first 2 min of cooling. Combining all methods (Method D) was the most effective at rapidly reducing temperature and providing sustained cooling throughout the duration of procurement, although the recorded WIT was not different between Methods (P = 0.36). Histological scores were different between the cooling Methods (P = 0.02) and the worst with Method A. There were differences in histological scores between Methods A and C (P = 0.02) and Methods A and D (P = 0.02), but not between Methods C and D (P = 0.95), which may highlight the importance of early cooling using an intraductal infusion. In conclusion, surface cooling alone cannot rapidly cool large (porcine or human) pancreata. Additional cooling with an intravascular flush and intraductal infusion results in improved core porcine pancreas temperature profiles during procurement and histopathology scores. These data may also have implications on human pancreas procurement as use of an intraductal infusion is not common practice.


A deubiquitinating enzyme encoded by HSV-1 belongs to a family of cysteine proteases that is conserved across the family Herpesviridae.
We have discovered a ubiquitin (Ub)-specific cysteine protease encoded within the N-terminal approximately 500 residues of the UL36 gene product, the largest (3164 aa) tegument protein of herpes simplex virus 1 (HSV-1). Enzymatic activity of this fragment, UL36USP, is detectable only after cleavage of UL36USP from full-length UL36 and occurs late during viral replication. UL36USP bears no homology to known deubiquitinating enzymes (DUBs) or Ub binding proteins. Sequence alignment of the large tegument proteins across the family Herpesviridae indicates conservation of key catalytic residues amongst these viruses. Recombinant UL36USP exhibits hydrolytic activity toward Ub-AMC and ubiquitinated branched peptides in vitro. In addition, recombinant UL36USP can cleave polyUb chains and appears to be specific for Lys48 linkages. Mutation of the active site cysteine residue (Cys65) to alanine abolishes this enzymatic activity. The lack of homology between UL36USP and eukaryotic DUBs makes this new family of herpesvirus ubiquitin-specific proteases attractive targets for selective inhibition.


Coexistence of genetically different Varroa destructor in Apis mellifera colonies.
The aim of this study was to investigate the genetic diversity of Varroa destructor parasitizing Apis mellifera colonies and to test for possible host-parasite association at the mitochondrial DNA (mtDNA) level. Six A. mellifera haplotypes (including a novel C2aa) and five haplotypes of V. destructor were detected in 29 analyzed colonies from eight sampling sites in Serbia. We revealed the presence of the K and S1 haplotypes as well as KS1 and KP1 heteroplasmic mite individuals in all localities, while the P1 haplotype was only found in four sampling sites. Significant differences in V. destructor genetic diversity were found at both apiary and colony levels, with mite haplotypes coexisting in almost all tested colonies. In addition, a significant correlation between the number of analyzed mites per colony and the number of identified V. destructor haplotypes was observed. However, no significant host-parasite relationship was found, suggesting that mites bearing different haplotypes as well as those heteroplasmic individuals are well adapted to the host, A. mellifera, independently of the identified haplotype present in each colony. Our results will contribute to future population and biogeographic studies concerning V. destructor infesting A. mellifera, as well as to better understanding their host-parasite relationship.