Prospective memory impairment in chronic heart failure.
Although cognitive deficits are common in patients with chronic heart failure (CHF), no study to date has investigated whether these deficits extend to the capacity to execute delayed intentions (prospective memory, PM). This is a surprising omission given the critical role PM plays in correctly implementing many important CHF self-care behaviors. The present study aimed to provide the first empirical assessment of PM function in people with CHF. The key dependent measure was a laboratory measure of PM that closely simulates PM tasks in daily life - Virtual Week. A group comparison design was used, with 30 CHF patients compared to 30 demographically matched controls. Background measures assessing executive functions, working memory, and verbal memory were also administered. The CHF group exhibited significant PM impairment, with difficulties generalizing across different types of PM tasks (event, time, regular, irregular). The CHF group also had moderate deficits on several of the background cognitive measures. Given the level of impairment remained consistent even on tasks that imposed minimal demands on memory for task content, CHF-related difficulties most likely reflects problems with the prospective component. However, exploratory analyses suggest that difficulties with retrospective memory and global cognition (but not executive control), also contribute to the PM difficulties seen in this group. The implications of these data are discussed, and in particular, it is argued that problems with PM may help explain why patient engagement in CHF self-care behaviors is often poor.


Superolateral Hoffa's fat pad edema: association with patellofemoral maltracking and impingement.
Nonelderly patients presenting with knee pain often have patellofemoral maltracking or impingement abnormalities. There is a relative paucity of literature on the incidence and significance of impingement-related edema of the superolateral aspect of Hoffa's (infrapatellar) fat pad in these cases. Our study was designed to systematically evaluate the correlation of superolateral Hoffa's fat pad edema with various anatomic parameters of trochlear morphology and patellar alignment. We evaluated 50 knee MRI examinations in 47 patients for the presence of edema in superolateral Hoffa's fat pad and associated anatomic abnormalities of the patellofemoral joint. Of the 50 examinations, 25 (50%) showed superolateral Hoffa's fat pad edema, and statistically significant differences were seen between those with and without edema with respect to sex (6/22 men vs 19/28 women) and patellar tendon patellar-length ratio (1.3 ± 0.16 and 1.1 ± 0.12 for those with and without edema, respectively). The findings in our study suggest that edema in superolateral Hoffa's fat pad may be an important indicator of underlying patellofemoral maltracking or impingement in younger, symptomatic patients.


Deep Reinforcement Learning for Multiparameter Optimization in de novo Drug Design.
In medicinal chemistry programs it is key to design and make compounds that are efficacious and safe. This is a long, complex, and difficult multiparameter optimization process, often including several properties with orthogonal trends. New methods for the automated design of compounds against profiles of multiple properties are thus of great value. Here we present a fragment-based reinforcement learning approach based on an actor-critic model, for the generation of novel molecules with optimal properties. The actor and the critic are both modeled with bidirectional long short-term memory (LSTM) networks. The AI method learns how to generate new compounds with desired properties by starting from an initial set of lead molecules and then improving these by replacing some of their fragments. A balanced binary tree based on the similarity of fragments is used in the generative process to bias the output toward structurally similar molecules. The method is demonstrated by a case study showing that 93% of the generated molecules are chemically valid and more than a third satisfy the targeted objectives, while there were none in the initial set.


Genetic diversity of infectious hematopoietic necrosis virus from Feather River and Lake Oroville, California, and virulence of selected isolates for Chinook salmon and rainbow trout.
Infectious hematopoietic necrosis virus (IHNV) is a significant pathogen of young salmonid fishes worldwide but particularly within the historical range of the Pacific Northwest and California. In the Sacramento and San Joaquin River drainages of California, IHNV outbreaks in juvenile Chinook salmon Oncorhynchus tshawytscha have been observed regularly at large production hatcheries, including Coleman National Fish Hatchery (established in 1941) and Feather River State Fish Hatchery (FRH; established in 1967), since facility operations began. Recent severe epidemics at the FRH in 1998 and 2000-2002 prompted investigations into the characteristics and potential sources of virus at this facility. Both phylogenetic analyses of a variable portion of the glycoprotein gene and serologic comparisons based on neutralization with three polyclonal rabbit sera were used to characterize 82 IHNV isolates from the Feather River watershed between 1969 and 2004. All isolates examined were in the L genogroup and belonged to one of three serologic groups typical of IHNV from California. The IHNV isolates from the Feather River area demonstrated a maximum nucleotide sequence divergence of 4.0%, and new isolates appeared to emerge from previous isolates rather than by the introduction of more diverse subgroups from exogenous sources. The earliest isolates examined from the watershed formed the subgroup LI, which disappeared coincidently with a temporal shift to new genetic and serologic types of the larger subgroup LII. Experimental challenges demonstrated no significant differences in the virulence for juvenile Chinook salmon and rainbow trout O. mykiss from selected isolates representing the principal types of IHNV found historically and from recent epidemics at FRH. While most isolates were equally virulent for both host species, one isolate was found to be more virulent for Chinook salmon than for rainbow trout.


Regulation of glycolysis and the Warburg effect in wound healing.
One of the most significant adverse postburn responses is abnormal scar formation, such as keloids. Despite its prolificacy, the underlying pathophysiology of keloid development is unknown. We recently demonstrated that NLRP3 inflammasome, the master regulator of inflammatory and metabolic responses (e.g., aerobic glycolysis), is essential for physiological wound healing. Therefore, burn patients who develop keloids may exhibit altered immunometabolic responses at the site of injury, which interferes with normal healing and portends keloid development. Here, we confirmed keloid NLRP3 activation (cleaved caspase-1 [P < 0.05], IL-1β [P < 0.05], IL-18 [P < 0.01]) and upregulation in Glut1 (P < 0.001) and glycolytic enzymes. Burn skin similarly displayed enhanced glycolysis and Glut1 expression (P < 0.01). However, Glut1 was significantly higher in keloid compared with nonkeloid burn patients (>2 SD above mean). Targeting aberrant glucose metabolism with shikonin, a pyruvate kinase M2 inhibitor, dampened NLRP3-mediated inflammation (cleaved caspase-1 [P < 0.05], IL-1β [P < 0.01]) and improved healing in vivo. In summary, burn skin exhibited evidence of Warburg-like metabolism, similar to keloids. Targeting this altered metabolism could change the trajectory toward normal scarring, indicating the clinical possibility of shikonin for abnormal scar prevention.


Nonlinear temporal dynamics of cerebral small vessel disease: The RUN DMC study.
To investigate the temporal dynamics of cerebral small vessel disease (SVD) by 3 consecutive assessments over a period of 9 years, distinguishing progression from regression. Changes in SVD markers of 276 participants of the Radboud University Nijmegen Diffusion Tensor and Magnetic Resonance Imaging Cohort (RUN DMC) cohort were assessed at 3 time points over 9 years. We assessed white matter hyperintensities (WMH) volume by semiautomatic segmentation and rated lacunes and microbleeds manually. We categorized baseline WMH severity as mild, moderate, or severe according to the modified Fazekas scale. We performed mixed-effects regression analysis including a quadratic term for increasing age. Mean WMH progression over 9 years was 4.7 mL (0.54 mL/y; interquartile range 0.95-5.5 mL), 20.3% of patients had incident lacunes (2.3%/y), and 18.9% had incident microbleeds (2.2%/y). WMH volume declined in 9.4% of the participants during the first follow-up interval, but only for 1 participant (0.4%) throughout the whole follow-up. Lacunes disappeared in 3.6% and microbleeds in 5.7% of the participants. WMH progression accelerated over time: including a quadratic term for increasing age during follow-up significantly improved the model (p < 0.001). SVD progression was predominantly seen in participants with moderate to severe WMH at baseline compared to those with mild WMH (odds ratio [OR] 35.5, 95% confidence interval [CI] 15.8-80.0, p < 0.001 for WMH progression; OR 5.7, 95% CI 2.8-11.2, p < 0.001 for incident lacunes; and OR 2.9, 95% CI 1.4-5.9, p = 0.003 for incident microbleeds). SVD progression is nonlinear, accelerating over time, and a highly dynamic process, with progression interrupted by reduction in some, in a population that on average shows progression.


Molecular and cellular mechanisms associated with autoimmune diseases.
Evidence points to increases in the incidence and prevalence of several autoimmune diseases in the United States. As a result, the cost to public health from clinical management of autoimmune conditions is on the rise. The initiation and progression of autoimmune disturbances involves both genetic and environmental factors. Deficiencies in important proteins that normally participate in maintaining checks and balances within the internal milieu may render an individual prone to developing autoantibodies. Structural abnormalities or decline in normal levels of the pentraxins (serum amylase-P protein, the acute phase proteins, complement, and C-reactive proteins) have been shown to induce autoimmunity. Irregular transmission of information arising from multiple signal transduction pathways typically associated with the serine/threonine cascade routes of mitogen activating phosphorylation kinases, has also been found to induce autoimmunity. The kind of ligand/receptor interactions drives physical recruitment of different signals within the lymphocyte; these links define the quality and quantity of subsequent immune responses. CD95 or the Fas/Apo-1 and its ligand CD95L participate in regulating lymphocyte populations and therefore influence various aspects of immune responses. Mutational abnormalities resulting from synthesis of proteins by the CD95 and/or its ligand CD95L may result in alterations in the apoptotic pathways. Apoptosis may be completely inhibited, activated or partially stimulated. Modulation of apoptosis may lead to accumulation of self-antigens. Subsequently the immune system may be stimulated to react against self-molecules through lymphatic hyperplasia. This process may end up in proliferative disorders and enhanced susceptibility to autoimmune syndromes. This paper deals with mechanisms of autoimmunopathogenesis at the cellular and molecular levels. Emphasis is laid on the role of T and B cell receptor/ligand interactions, functions and malfunctions due to structural and quantitative alterations in T- B- cell clusterof antigen determinants. Genetically susceptible patients who develop spontaneous autoimmune diseases are examined and the etiological factors implicated in the initiation and subsequent dissemination of autoimmune diseases is discussed.


A hidden Markov model to predict early mastitis from test-day somatic cell scores.
In many countries, high somatic cell scores (SCS) in milk are used as an indicator for mastitis because they are collected on a routine basis. However, individual test-day SCS are not very accurate in identifying infected cows. Mathematical models may improve the accuracy of the biological marker by making better use of the information contained in the available data. Here, a simple hidden Markov model (HMM) is described mathematically and applied to SCS recorded monthly on cows with or without clinical mastitis to evaluate its accuracy in estimating parameters (mean, variance and transition probabilities) under healthy or diseased states. The SCS means were estimated at 1.96 (s.d. = 0.16) and 4.73 (s.d. = 0.71) for the hidden healthy and infected states, and the common variance at 0.83 (s.d. = 0.11). The probability of remaining uninfected, recovering from infection, getting newly infected and remaining infected between consecutive test days was estimated at 78.84%, 60.49%, 11.70% and 15%, respectively. Three different health-related states were compared: clinical stages observed by farmers, subclinical cases defined for somatic cell counts below or above 250 000 cells/ml and infected stages obtained from the HMM. The results showed that HMM identifies infected cows before the appearance of clinical and subclinical signs, which may critically improve the power of the studies on the genetic determinants of SCS and reduce biases in predicting breeding values for SCS.


New genus of opecoelid trematode from Pristipomoides aquilonaris (Perciformes: Lutjanidae) and its phylogenetic affinity within the family Opecoelidae.
Bentholebouria colubrosa gen. n. et sp. n. (Digenea: Opecoelidae) is described in the wenchman, Pristipomoides aquilonaris (Goode et Bean), from the eastern Gulf of Mexico, and new combinations are proposed: Bentholebouria blatta (Bray et Justine, 2009) comb. n., Bentholebouria longisaccula (Yamaguti, 1970) comb. n., Bentholebouria rooseveltiae (Yamaguti, 1970) comb. n., and Bentholebouria ulaula (Yamaguti, 1970) comb. n. The new genus is morphologically similar to Neolebouria Gibson, 1976, but with a longer cirrus sac, entire testes, a rounded posterior margin with a cleft, and an apparent restriction to the deepwater snappers. Morphologically, the new species is closest to B. blatta from Pristipomoides argyrogrammicus (Valenciennes) off New Caledonia but can be differentiated by the nature of the internal seminal vesicle (2-6 turns or loops rather than constrictions), a longer internal seminal vesicle (occupying about 65% rather than 50% of the cirrus sac), a cirrus sac that extends further into the hindbody (averaging 136% rather than 103% of the distance from the posterior margin of the ventral sucker to the ovary), and a narrower body (27% rather than 35% mean width as % of body length). A Bayesian inference analysis of partial sequence of the 28S rDNA from Neolebouria lanceolata (Price, 1934), Cainocreadium lintoni (Siddiqi et Cable, 1960), Hamacreadium mutabile Linton, 1910, Opecoeloides fimbriatus (Linton, 1910), Podocotyloides brevis Andres et Overstreet, 2013, the new species, and previously published comparable sequences from 10 opecoelid species revealed two clades. One clade includes deep-sea (> or = 200 m) and freshwater fish opecoelids + Opecoeloides Bremser in Rudolphi, 1819, and a second clade included those opecoelids from shallow-water marine, perciform fishes.


A randomized controlled trial of variable rate phenylephrine infusion with rescue phenylephrine boluses versus rescue boluses alone on physician interventions during spinal anesthesia for elective cesarean delivery.
Phenylephrine infusion is used to reduce hypotension during spinal anesthesia for cesarean delivery. A prophylactic fixed rate infusion regimen may not improve hemodynamic control; a variable rate regimen adjusted in response to changes in arterial blood pressure and heart rate may allow more accurate maintenance of baseline blood pressure. We hypothesized that a combination of crystalloid solution coload with a variable rate phenylephrine infusion and phenylephrine rescue boluses may be associated with fewer physician interventions needed to maintain maternal systolic blood pressure within 20% of baseline and greater hemodynamic stability than crystalloid solution coload with phenylephrine rescue boluses alone. In this prospective, double-blind study, 80 patients received a coload with 15 mL/kg lactated Ringer's solution immediately after the initiation of spinal anesthesia. Patients were randomized to receive a prophylactic variable rate phenylephrine infusion starting at 0.75 μg/kg/min (group P) or infusion of normal saline (group S). Maternal systolic blood pressure was maintained within 20% of baseline with rescue phenylephrine boluses using a preset algorithm. During the predelivery period, the number of physician interventions (primary outcome), hemodynamic performance, nausea/vomiting, and umbilical cord blood gas values were compared between the groups. One patient from group S was excluded due to protocol violation. Therefore, group P included 40 patients and group S 39 patients. The median (range) number of physician interventions needed to maintain maternal hemodynamics within the target range (0 [0-6] vs 3 [0-9], difference in median: 3, 95% confidence interval of difference: 2-4) and incidence of hypotension (8/40 [20%] vs 35/39 [90%]) were lower in group P compared with group S (P < 0.001). Group P had a higher incidence of hypertension compared with group S (6/40 [15%] vs 0/39 [0%], P = 0.026). The median performance error was closer to baseline (P < 0.001) with a smaller median absolute performance error (P = 0.001) in group P versus group S. In group P, 4/40 (10%) patients had nausea/vomiting compared with 17/39 (44%) in group S (P = 0.001). The number needed to treat was 1.4 women to prevent 1 case of hypotension, and 3 women to prevent 1 case of nausea/vomiting; the rate of hypertension was 1 case per 6.7 women treated. Neonatal outcomes were not different between the 2 groups. Prophylactic variable rate phenylephrine infusion and rescue phenylephrine bolus dosing is more effective than relying on rescue phenylephrine bolus dosing with respect to limiting clinician workload and maternal symptoms during spinal anesthesia for cesarean delivery.


Lowering the pKa of a bisimidazoline lead with halogen atoms results in improved activity and selectivity against Trypanosoma brucei in vitro.
Diphenyl-based bis(2-iminoimidazolidines) are promising antiprotozoal agents that are curative in mouse models of stage 1 trypanosomiasis but devoid of activity in the late-stage disease, possibly due to poor brain penetration caused by their dicationic nature. We present here a strategy consisting in reducing the pKa of the basic 2-iminoimidazolidine groups though the introduction of chlorophenyl, fluorophenyl and pyridyl ring in the structure of the trypanocidal lead 4-(imidazolidin-2-ylideneamino)-N-(4-(imidazolidin-2-ylideneamino)phenyl)benzamide (1). The new compounds showed reduced pKa values (in the range 1-3 pKa units) for the imidazolidine group linked to the substituted phenyl ring. In vitro activities (EC50) against wild type and resistant strains of T. b. brucei (s427 and B48, respectively) were in the submicromolar range with four compounds being more active and selective than 1 (SI > 340). In particular, the two most potent compounds (3b and 5a) acted approximately 6-times faster than 1 to kill trypanosomes in vitro. No cross-resistance with the diamidine and melaminophenyl class of trypanocides was observed indicating that these compounds represent interesting leads for further in vivo studies.


One year after mild injury: comparison of health status and quality of life between patients with whiplash versus other injuries.
To compare health status, effect on family, occupational consequences, and quality of life (QOL) 1 year after an accident between patients with whiplash versus other mild injuries, and to explore the relationship between initial injury (whiplash vs other) and QOL. This was a prospective cohort study. The study used data from the ESPARR cohort (a representative cohort of road accident victims) and included 173 individuals with "pure" whiplash and 207 with other mild injuries. QOL at 1-year followup was assessed on the World Health Organization Quality of Life questionnaire. Correlations between explanatory variables and QOL were explored by Poisson regression to provide adjusted relative risks, with ANOVA for the various QOL scores explored. One year post-accident, more patients who had whiplash than other casualties complained of nonrecovery of health status (56% vs 43%) and of the occupational effect of pain (31% vs 23%). QOL and posttraumatic stress disorder (PTSD) were similar in the 2 groups. Impaired QOL did not correlate with whiplash when models were adjusted on sociodemographic variables and history of psychological distress. Whatever the initial lesion, PTSD was a determining factor for poorer QOL. Sociodemographic factors, preaccident psychological history prior to the accident, and PTSD were the main factors influencing QOL, rather than whether the injury was whiplash. PTSD may also be related to pain.


A realizable renewable energy future
The ability of renewable resources to provide all of society's energy needs is shown by using the United States as an example. Various renewable systems are presented, and the issues of energy payback, carbon dioxide abatement, and energy storage are addressed. Pathways for renewable hydrogen generation are shown, and the implementation of hydrogen technologies into the energy infrastructure is presented. The question is asked, Should money and energy be spent on carbon dioxide sequestration, or should renewable resources be implemented instead.


Awareness of deficits in traumatic brain injury: a multidimensional approach to assessing metacognitive knowledge and online-awareness.
Recent models of impaired awareness in brain injury draw a distinction between metacognitive knowledge of difficulties and online awareness of errors (emergent and anticipatory). We examined performance of 31 Traumatic Brain Injury (TBI) participants and 31 healthy controls using a three-strand approach to assessing awareness. Metacognitive knowledge was assessed with an awareness interview and discrepancy scores on three questionnaires--Patient Competency Rating Scale, Frontal Systems Behavioral Scale and the Cognitive Failures Questionnaire. Online Emergent Awareness was assessed using an online error-monitoring task while participants performed tasks of sustained attention. Online anticipatory awareness was examined using prediction performance on two cognitive tasks. Results indicated that the TBI Low Self-Awareness (SA) group and High SA group did not differ in terms of severity, chronicity or standard neuropsychological tasks but those with Low SA were more likely to exhibit disinhibition, interpersonal problems and more difficulties in total competency. Sustained attention abilities were associated with both types of online awareness (emergent and anticipatory). There was a strong relationship between online emergent and online anticipatory awareness. Metacognitive knowledge did not correlate with the other two measures. This study highlights the necessity in adopting a multidimensional approach to assessing the multifaceted phenomenon of awareness of deficits.


Impact of Human Resources on Implementing an Evidence-Based HIV Prevention Intervention.
Evidence-based interventions (EBIs) often require competent staff, or human resources (HR), for implementation. The empirical evidence characterizing the influence of HR fluctuations on EBI delivery is limited and conflicting. Using the Interactive Systems Framework, we explored staff fluctuation and the subsequent influence on RESPECT, an HIV prevention EBI. We conducted interviews with staff in two waves (n = 53, Wave I; n = 37, Wave II) in a national sample of organizations delivering RESPECT (N = 29). We analyzed interviews qualitatively to describe changes among RESPECT staff and explore the subsequent influences on RESPECT implementation. Organizations reported downsizing, turnover, and expansion of staff positions. Staff changes had multiple influences on RESPECT implementation including clients reached, fidelity to specific RESPECT protocols, and overall sustainability of RESPECT over time. HR fluctuations are common, and our analyses provide an initial characterization of the relationship between HR fluctuation and EBI implementation. Given the prominent influence of HR on EBI implementation, the Interactive Systems Framework is a useful guiding tool for future examinations.


Protein kinase C mediates experimental colitis in the rat.
Protein kinase C (PKC) plays an important role in the cell signal transduction of many physiological processes. In contrast to these physiological responses, increases in PKC activity have also been associated with inflammatory disease states, including ulcerative colitis. The objective of this study was to examine the role of PKC as a causative mediator in initiation of experimentally induced colitis in the rat. Colitis was induced in rats by intrarectal (0.6 ml) instillation of 2,4,6-trinitrobenzenesulfonic acid (TNBS; 75 mg/kg in 50% ethanol) or the PKC activator phorbol 12-myristate 13-acetate (PMA; 1.5-3.0 mg/kg in 20% ethanol). Gross and histological mucosal damage, mucosal neutrophil infiltration, mucosal PKC activity, and PKC protein content for PKC isoforms alpha, beta, delta, and epsilon were assessed 2 h to 14 days after an inflammatory challenge. Both PKC activity and mucosal injury increased significantly within 4 h of TNBS treatment. PKC activity was maximal at 7 days and declined at 14 days, whereas mucosal damage became maximal at 1 day and declined after 7 days. In contrast, neutrophil infiltration as assessed by myeloperoxidase activity only increased 12 h after TNBS treatment, became maximal 1 day after TNBS administration, and declined thereafter. PKCbeta, -delta, and -epsilon were increased in response to TNBS, whereas PKCalpha protein content was decreased. The PKC antagonists staurosporine and GF-109203X (25 ng/kg iv) reduced TNBS-induced changes in mucosal PKC activity and the degree of mucosal damage. In contrast, neutropenia induced by antineutrophil serum treatment did not significantly affect the degree of injury or mucosal PKC activity. Furthermore, activation of mucosal PKC activity with PMA also induced mucosal damage, which was also inhibited by pretreatment with a PKC antagonist. In conclusion, these results suggest that increases in PKC activity play a causative role in TNBS-induced colitis. The PKC-mediated response to TNBS does not appear to involve neutrophil infiltration.


School health implementation tools: a mixed methods evaluation of factors influencing their use.
The U.S. Centers for Disease Control and Prevention (CDC) develops tools to support implementation of evidence-based interventions for school health. To advance understanding of factors influencing the use of these implementation tools, we conducted an evaluation of state, school district, and local school staffs' use of four CDC tools to support implementation of physical activity, nutrition, health education, and parent engagement. Two frameworks guided the evaluation: Interactive Systems Framework (ISF) for Dissemination and Implementation and Consolidated Framework for Implementation Research (CFIR). The evaluation applied a mixed methods, cross-sectional design that included online surveys (n = 69 state staff from 43 states), phone interviews (n = 13 state staff from 6 states), and in-person interviews (n = 90 district and school staff from 8 districts in 5 states). Descriptive analyses were applied to surveys and content analysis to interviews. The survey found that the majority of state staff surveyed was aware of three of the CDC tools but most were knowledgeable and confident in their ability to use only two. These same two tools were the ones for which states were most likely to have provided training and technical assistance in the past year. Interviews provided insight into how tools were used and why use varied, with themes organized within the ISF domain "support strategies" (e.g., training, technical assistance) and four CFIR domains: (1) characteristics of tools, (2) inner setting, (3) outer setting, and (4) individuals. Overall, tools were valued for the credibility of their source (CDC) and evidence strength and quality. Respondents reported that tools were too complex for use by school staff. However, if tools were adaptable and compatible with inner and outer setting factors, state and district staff were willing and able to adapt tools for school use. Implementation tools are essential to supporting broad-scale implementation of evidence-based interventions. This study illustrates how CFIR and ISF might be applied to evaluate factors influencing tools' use and provides recommendations for designing tools to fit within the multi-tiered systems involved in promoting, supporting, and implementing evidence-based interventions in schools. Findings have relevance for the design of implementation tools for use by other multi-tiered systems.


Assessment of the microbial diversity of Chinese Tianshan tibicos by single molecule, real-time sequencing technology.
Chinese Tianshan tibico grains were collected from the rural area of Tianshan in Xinjiang province, China. Typical tibico grains are known to consist of polysaccharide matrix that embeds a variety of bacteria and yeasts. These grains are widely used in some rural regions to produce a beneficial sugary beverage that is slightly acidic and contains low level of alcohol. This work aimed to characterize the microbiota composition of Chinese Tianshan tibicos using the single molecule, real-time sequencing technology, which is advantageous in generating long reads. Our results revealed that the microbiota mainly comprised of the bacterial species of Lactobacillus hilgardii, Lactococcus raffinolactis, Leuconostoc mesenteroides, Zymomonas mobilis, together with a Guehomyces pullulans-dominating fungal community. The data generated in this work helps identify beneficial microbes in Chinese Tianshan tibico grains.


Effectiveness of patient delivered partner medication for preventing recurrent Chlamydia trachomatis.
To determine if providing Chlamydia trachomatis infected women with medication to deliver to their sex partner(s) could reduce recurrent chlamydia infections compared with the standard partner referral method. A observational cohort study of 178 women, 14-39 years old attending a family planning clinic, diagnosed and treated for C trachomatis between October 1993 and December 1994 was conducted (43 received patient delivered partner medication (PDPM) and 135 received partner referral cards). Women were retested before or at their annual visit. The mean time of follow up was 17.7 months (SD 7.7). The PDPM group (n = 43) was similar to partner referral group (n = 135) for age, race, contraceptive method, history of an STD, and follow up time. The annual recurrent infection rate was lower among the PDPM group compared with the partner referral group (11.5% v 25.5%, p < 0.05). After adjusting for age in logistic regression, women in the PDPM group were less likely than women in the partner referral group to have an incident C trachomatis infection (OR 0.37, 95% CI 0.15-0.97, p < 0.05). These findings suggest that patient delivered partner medication can protect women from recurrent C trachomatis infection compared with the standard partner referral approach. Prospective studies with larger sample sizes are under way.


Lower urinary tract symptom prevalence and management among patients with multiple sclerosis.
This study was conducted to assess self-reported prevalence and management of lower urinary tract symptoms (LUTS), along with drivers of treatment seeking, among patients with multiple sclerosis (MS). An online, cross-sectional survey was administered to US-residing participants with self-reported MS to assess presence of LUTS, including urinary incontinence (UI). Participants experiencing LUTS were asked additional questions related to management and current therapies. Multivariate logistic regression identified drivers of treatment-seeking behavior. A total of 1052 participants completed the survey; 1047 were included in the analysis. Nine hundred sixty-six participants (92%) reported at least one LUTS, the most common being post-micturition dribble (64.9%), urinary urgency (61.7%), and a feeling of incomplete emptying (60.7%). Eight hundred twenty-six (79%) reported having some type of UI. Of those with any type of LUTS, 70% (n = 680) had previously discussed urinary symptoms with a health-care provider (HCP), while only 32% (n = 311) had seen an HCP in the past year. Logistic regression found urgency (odds ratio [OR] 1.20 [95% confidence interval (CI), 1.00-1.44]), intermittent urine stream (OR 1.40 [95% CI, 1.15-1.69]), and urgency UI (OR 1.78 [95% CI, 1.22-2.60]) to be significant predictors of seeking treatment. Of those who had discussed LUTS with an HCP, 480 (70.6%) were currently receiving at least one LUTS treatment; the most common treatments were reducing fluid intake, pelvic exercises, oral anticholinergic medications, and avoiding certain foods/alcohol. LUTS are commonly experienced among people with MS but are largely untreated. Proper LUTS assessment and work-up is warranted in MS patients.


Work-organisational and personal factors associated with upper body musculoskeletal disorders among sewing machine operators.
To assess the contribution of work-organisational and personal factors to the prevalence of work-related musculoskeletal disorders (WMSDs) among garment workers in Los Angeles. This is a cross-sectional study of self-reported musculoskeletal symptoms among 520 sewing machine operators from 13 garment industry sewing shops. Detailed information on work-organisational factors, personal factors, and musculoskeletal symptoms were obtained in face-to-face interviews. The outcome of interest, upper body WMSD, was defined as a worker experiencing moderate or severe musculoskeletal pain. Unconditional logistic regression models were adopted to assess the association between both work-organisational factors and personal factors and the prevalence of musculoskeletal pain. The prevalence of moderate or severe musculoskeletal pain in the neck/shoulder region was 24% and for distal upper extremity it was 16%. Elevated prevalence of upper body pain was associated with age less than 30 years, female gender, Hispanic ethnicity, being single, having a diagnosis of a MSD or a systemic illness, working more than 10 years as a sewing machine operator, using a single sewing machine, work in large shops, higher work-rest ratios, high physical exertion, high physical isometric loads, high job demand, and low job satisfaction. Work-organisational and personal factors were associated with increased prevalence of moderate or severe upper body musculoskeletal pain among garment workers. Owners of sewing companies may be able to reduce or prevent WMSDs among employees by adopting rotations between different types of workstations thus increasing task variety; by either shortening work periods or increasing rest periods to reduce the work-rest ratio; and by improving the work-organisation to control psychosocial stressors. The findings may guide prevention efforts in the garment sector and have important public health implications for this workforce of largely immigrant labourers.


Evaluation of early discharge after hospital treatment of neutropenic fever in acute myeloid leukemia (AML).
Hospital admission for neutropenic fever in patients with AML is a standard practice. However, discharge practices vary once patients become afebrile, with many patients hospitalized until rise in the absolute neutrophil count (ANC) to >500 (ANC recovery). Data to support this practice are sparse. We hypothesized that patients admitted for neutropenic fever, particularly if in complete remission (CR) or about to enter CR following the chemotherapy course associated with neutropenic fever, might be safely discharged earlier (ED). Benefits of ED are less exposure to hospital pathogens, reduced cost, increased availability of beds for patients more in need of urgent care, and potentially, enhanced psychological well-being. We identified patients age 18-70 with newly diagnosed AML who were admitted to the University of Washington Medical Center with neutropenic fever between January 2008 and May 2010. We compared subsequent (within 30 days of discharge) deaths, intensive care unit (ICU) admissions, and readmissions for neutropenic fever according to discharge ANC, regarded as a numerical variable using the Mann-Whitney U test and as <500 vs >500 using the Fisher Exact test. We used the Mann-Whitney U or Spearman correlation to analyze the relation between ANC at discharge and other covariates that might have affected outcome: age, ECOG performance status at admission for neutropenic fever, days inpatient, remission status, and type of infection (pneumonia, gram negative bacteremia, others). We evaluated 49 patients discharged after admission for neutropenic fever, 26 of whom were discharged with an ANC <500. Thirty five of the patients were in CR or entered CR following the chemotherapy course associated with their neutropenic fever admission. Patients who were discharged with lower ANC were more likely to be readmitted with neutropenic fever (Mann-Whitney U p=0.03), although this was not true using ANC categorized as < vs >500 (Fisher Exact p=0.24, 95% confidence interval -0.47, 0.11). There was no relation between ANC at discharge and subsequent admission to an ICU (Mann-Whitney U p=0.50, Fisher Exact p=0.64, 95% confidence interval 0.2, 0.34 using the 500 ANC cut off). One patient died: a 55 year old discharged with ANC 0 after successful treatment of neutropenic fever died 19 days after hospital readmission with fever of unknown origin. Stenotrophomonas maltophilia pneumonia and sepsis were discovered 14 days after readmission. Assuming a beta distribution and rates of death of 1/26 for discharge with ANC<500 and 0/23 for discharge with ANC>500, the probability that a discharge ANC with <500 is associated with a higher death rate is 0.019. The number of events was too small for a multivariate analysis. However, patients with better performance status (<ECOG 2) or who spent a shorter time in hospital after admission for neutropenic fever were more likely to be discharged with lower ANC (Fisher exact p=0.09 and Spearman p=0.02 respectively), while the likelihood of discharge with ANC<500 was unrelated to age, remission status, or type of infection. Thus we examined the relation between ANC and readmission for neutropenic fever separately in patients with better or worse performance status and in patients who spent more or less than the median time (8 days) in hospital after admission for neutropenic fever. This analysis indicated that patients discharged with lower ANC were more likely to be readmitted only if they had spent more than 8 days in hospital or if they were performance status <2. Our results suggest that an ANC of 500 is an excessively high cut off for discharge following hospitalization for neutropenic fever. The rate of rise of the ANC, as well as its absolute value, may also play a role.


Msn2p, a zinc finger DNA-binding protein, is the transcriptional activator of the multistress response in Saccharomyces cerevisiae.
The stress response promoter element (STRE) confers increased transcription to a set of genes following environmental or metabolic stress in Saccharomyces cerevisiae. A lambda gt11 library was screened to isolate clones encoding STRE-binding proteins, and one such gene was identified as MSN2, which encoded a zinc-finger transcriptional activator. Disruption of the MSN2 gene abolished an STRE-binding activity in crude extracts as judged by both gel mobility-shift and Southwestern blot experiments, and overexpression of MSN2 intensified this binding activity. Northern blot analysis demonstrated that for the known or suspected STRE-regulated genes DDR2, CTT1, HSP12, and TPS2, transcript induction was impaired following heat shock or DNA damage treatment in the msn2-disrupted strain and was constitutively activated in a strain overexpressing MSN2. Furthermore, heat shock induction of a STRE-driven reporter gene was reduced more than 6-fold in the msn2 strain relative to wild-type cells. Taken together, these data indicate that Msn2p is the transcription factor that activates STRE-regulated genes in response to stress. Whereas nearly 85% of STRE-mediated heat shock induction was MSN2 dependent, there was significant MSN2-independent expression. We present evidence that the MSN2 homolog, MSN4, can partially replace MSN2 for transcriptional activation following stress. Moreover, our data provides evidence for the involvement of additional transcription factors in the yeast multistress response.


Coronally Advanced Flap Technique to Treat Class I and II Gingival Recession in Combination with Connective Tissue Graft or Equine Collagen Matrix: A Retrospective Study.
This retrospective study aimed to compare the effectiveness of an equine collagen matrix (ECM) with that of a subepithelial connective tissue graft (CTG) in patients affected by Class I and II gingival recessions treated with a coronally advanced flap (CAF) technique. Records of 50 consecutive patients were analyzed. Recession depth, probing depth, keratinized tissue width, and percentage of root coverage had been recorded at baseline and at the 1-year follow-up. The number of patients that achieved complete root coverage was also assessed. According to the investigated parameters, ECM and CTG provide similar results when used in association with a CAF technique.


Protein kinase A phosphorylation of the multifunctional protein CAD antagonizes activation by the MAP kinase cascade.
The flux through the de novo pyrimidine biosynthetic pathway is controlled by the multifunctional protein CAD, which catalyzes the first three steps. The cell cycle dependent regulation of pyrimidine biosynthesis is a consequence of sequential phosphorylation of CAD Thr456 and Ser1406 by the MAP kinase and PKA cascades, respectively. Coordinated regulation of the pathway requires precise timing of the two phosphorylation events. These studies show that phosphorylation of purified CAD by PKA antagonizes MAP kinase phosphorylation, and vice versa. Similar results were observed in vivo. Forskolin activation of PKA in BHK-21 cells resulted in a 8.5 fold increase in Ser1406 phosphorylation and severely curtailed the MAP kinase mediated phosphorylation of CAD Thr456. Moreover, the relative activity of MAP kinase and PKA was found to determine the extent of Thr456 phosphorylation. Transfectants expressing elevated levels of MAP kinase resulted in a 11-fold increase in Thr456 phosphorylation, whereas transfectants that overexpress PKA reduced Thr456 phosphorylation 5-fold. While phosphorylation of one site by one kinase may induce conformational changes that interfere with phosphorylation by the other, the observation that both MAP kinase and PKA form stable complexes with CAD suggest that the mutual antagonism is the result of steric interference by the bound kinases. The reciprocal antagonism of CAD phosphorylation by MAP kinase and PKA provides an elegant mechanism to coordinate the cell cycle-dependent regulation of pyrimidine biosynthesis ensuring that signals for up- and down-regulation of the pathway do not conflict.


Impact of a Mesoporous Titania-Perovskite Interface on the Performance of Hybrid Organic-Inorganic Perovskite Solar Cells.
We report on the optimization of the interfacial properties of titania in mesoscopic CH3NH3PbI3 solar cells. Modification of the mesoporous TiO2 film by TiCl4 treatment substantially reduced the surface traps, as is evident from the sharpness of the absorption edge with a significant reduction in Urbach energy (from 320 to 140 meV) determined from photothermal deflection spectroscopy, and led to an order of magnitude enhancement in the bulk electron mobility and corresponding decrease in the transport activation energy (from 170 to 90 meV) within a device. After optimization of the photoanode-perovskite interface using various sizes of TiO2 nanoparticles, the best photovoltaic efficiency of 16.3% was achieved with the mesoporous TiO2 composed of 36 nm sized nanoparticles. The improvement in device performance can be attributed to the enhanced charge collection efficiency that is driven by improved charge transport in the mesoporous TiO2 layer. Also, the decreased recombination at the TiO2-perovskite interface and better perovskite coverage play important roles.


Adaptation to hard-object feeding in sea otters and hominins.
The large, bunodont postcanine teeth in living sea otters (Enhydra lutris) have been likened to those of certain fossil hominins, particularly the 'robust' australopiths (genus Paranthropus). We examine this evolutionary convergence by conducting fracture experiments on extracted molar teeth of sea otters and modern humans (Homo sapiens) to determine how load-bearing capacity relates to tooth morphology and enamel material properties. In situ optical microscopy and x-ray imaging during simulated occlusal loading reveal the nature of the fracture patterns. Explicit fracture relations are used to analyze the data and to extrapolate the results from humans to earlier hominins. It is shown that the molar teeth of sea otters have considerably thinner enamel than those of humans, making sea otter molars more susceptible to certain kinds of fractures. At the same time, the base diameter of sea otter first molars is larger, diminishing the fracture susceptibility in a compensatory manner. We also conduct nanoindentation tests to map out elastic modulus and hardness of sea otter and human molars through a section thickness, and microindentation tests to measure toughness. We find that while sea otter enamel is just as stiff elastically as human enamel, it is a little softer and tougher. The role of these material factors in the capacity of dentition to resist fracture and deformation is considered. From such comparisons, we argue that early hominin species like Paranthropus most likely consumed hard food objects with substantially higher biting forces than those exerted by modern humans.


The role of the carotenoids, lutein and zeaxanthin, in protecting against age-related macular degeneration: a review based on controversial evidence.
A review of the role of the carotenoids, lutein and zeaxanthin, and their function in altering the pathogenesis of age-related macular degeneration (AMD). Medline and Embase search. Recent evidence introduces the possibility that lutein and zeaxanthin, carotenoids found in a variety of fruits and vegetables may protect against the common eye disease of macular degeneration. This potential and the lack to slow the progression of macular degeneration, has fueled high public interest in the health benefits of these carotenoids and prompted their inclusion in various supplements. The body of evidence supporting a role in this disease ranges from basic studies in experimental animals to various other clinical and epidemiological studies. Whilst some epidemiological studies suggest a beneficial role for carotenoids in the prevention of AMD, others are found to be unrelated to it. Results of some clinical studies indicate that the risk for AMD is reduced when levels of the carotenoids are elevated in the serum or diet, but this correlation is not observed in other studies. Published data concerning the toxicity of the carotenoids or the optimum dosage of these supplements is lacking. An intake of dietary supplied nutrients rich in the carotenoids, lutein and zeaxanthin, appears to be beneficial in protecting retinal tissues, but this is not proven. Until scientifically sound knowledge is available we recommend for patients judged to be at risk for AMD to: alter their diet to more dark green leafy vegetables, wear UV protective lenses and a hat when outdoors. Future investigations on the role of nutrition, light exposure, genetics, and combinations of photodynamic therapy with intravitreal steroid (triamcinolone-acetonide) injections hold potential for future treatment possibilities.


Maltose chemoreceptor of Escherichia coli.
Strains carrying mutations in the maltose system of Escherichia coli were assayed for maltose taxis, maltose uptake at 1 and 10 muM maltose, and maltose-binding activity released by osmotic shock. An earlier conclusion that the metabolism of maltose is not necessary for chemoreception is extended to include the functioning of maltodextrin phosphorylase, the product of malP, and the genetic control of the maltose receptor by the product of malT is confirmed. Mutants in malF and malK are defective in maltose transport at low concentrations as well as high concentrations, as previously shown, but are essentially normal in maltose taxis. The product of malE has been previously shown to be the maltose-binding protein and was implicated in maltose transport. Most malE mutants are defective in maltose taxis, and all those tested are defective in maltose transport at low concentrations. Thus, as previously suggested, the maltose-binding protein probably serves as the recognition component of the maltose receptor, as well as a component of the transport system. tsome malE mutants release maltose-binding activity and are tactic toward maltose, although defective in maltose transport, implying that the binding protein has separate sites for interaction with the chemotaxis and transport systems. Some mutations in lamB, whose product is the receptor for the bacteriophage lamba, cause defects in maltose taxis, indicating some involvement of that product in maltose reception.


[Sociodemographic Factors Related to Plasma Concentrations of 25-OH Vitamin D and PTH in Cord Blood].
Plasma 25(OH)D levels in the newborn are dependent on maternal stores, thus, neonates of vitamin D-deficient mothers present a greater risk of hypocalcaemia, rickets and infections the first year of life. Several studies showing a high prevalence of vitamin D deficiency in pregnant women have been published recently. The aim of the study is to analyze the levels of 25(OH)D in cord blood and determine whether there is a relation with nutritional, socioeconomic and clinical factors of pregnant women and their newborns. Between March and May 2013, 99 pregnant women were recruited in Hospital del Mar (Barcelona), in whom plasma 25(OH)D and PTH levels were measured in cord blood at birth. Clinical history data were collected and a nutritional survey was made on maternal vitamin D and calcium intake and sun exposure. Statistical analysis was performed using SPSS. Comparisons were performed using Kruskal-Wallis and Mann-Whitney U tests, and correction for multiple comparisons using Bonferroni. P value <0.05 and <0.0083 for multiple comparisons were considered statistically significant. Mean 25(OH)D value in cord blood was 10.4 ± 6 .1 ng/ml. 94% of pregnant women had 25(OH)D levels in cord blood <20 ng/ml. Vitamin D and calcium intake was considered adequate in 92% although sun exposure was deficient in 47%. A correlation between serum 25(OH)D and vitamin D (p 0.033) and calcium intake (p 0.005), sun exposure (p<0.001), ethnicity (p<0.001), skin phototype (p<0.001) and use of traditional clothing (p<0.001) was found. There is a high prevalence of low levels of vitamin D after winter months in cord blood. The lowest 25(OH D levels were observed in Indo-Pakistani ethnicity, dark phototype and deficient sun exposure.


Extended-release naltrexone to prevent relapse among opioid dependent, criminal justice system involved adults: rationale and design of a randomized controlled effectiveness trial.
Extended-release naltrexone (XR-NTX, Vivitrol; Alkermes Inc.) is an injectable monthly sustained-release mu opioid receptor antagonist. XR-NTX is a potentially effective intervention for opioid use disorders and as relapse prevention among criminal justice system (CJS) populations. This 5-site open-label randomized controlled effectiveness trial examines whether XR-NTX reduces opioid relapse compared with treatment as usual (TAU) among community dwelling, non-incarcerated volunteers with current or recent CJS involvement. The XR-NTX arm receives 6 monthly XR-NTX injections at Medical Management visits; the TAU group receives referrals to available community treatment options. Assessments occur every 2 weeks during a 24-week treatment phase and at 12- and 18-month follow-ups. The primary outcome is a relapse event, defined as either self-report or urine toxicology evidence of ≥10 days of opioid use in a 28-day (4 week) period, with a positive or missing urine test counted as 5 days of opioid use. We describe the rationale, specific aims, and design of the study. Alternative design considerations and extensive secondary aims and outcomes are discussed. XR-NTX is a potentially important treatment and relapse prevention option among persons with opioid dependence and CJS involvement. ClinicalTrials.gov: NCT00781898.


Tolerance of bitter compounds by an herbivore,Cavia porcellus.
Many plant defensive chemicals are bitter to humans. Because of this taste characteristic, and because bitter compounds are often toxic, such substances, and the plants that contain them, are regarded as generally unpalatable to wildlife. These assumptions may be unwarranted. To test the hypothesis that herbivores are indifferent to 'bitter' tastants, we investigated the responsiveness of guinea pigs (Cavia porcellus) to denatonium benzoate, denatonium saccharide, limonene,L-phenylalanine, naringin, quebracho, quinine, Ro-Pel (a commercial animal repellent containing denatonium saccharide) and sucrose octaacetate. Only quinine and sucrose octaacetate slightly but significantly reduced feeding (P<0.05). Our findings are inconsistent with the notion that herbivores generally avoid what humans describe as bitter tastes.


Acute Exposure to Permethrin Modulates Behavioral Functions, Redox, and Bioenergetics Parameters and Induces DNA Damage and Cell Death in Larval Zebrafish.
Permethrin (PM) is a synthetic pyrethroid insecticide widely used as domestic repellent. Damage effects to nontarget organisms have been reported, particularly in the early stages of development. Studies indicate redox unbalance as secondary PM effect. Therefore, our goal was to investigate the acute PM effects on larval zebrafish. Larvae (6 days postfertilization) were exposed to PM (25-600 μg/L) during 24 hours, and 50% lethal concentration was estimated. For subsequent assays, the sublethal PM concentrations of 25 and 50 μg/L were used. PM increased anxiety-like behaviors according to the Novel Tank and Light-Dark tests. At the molecular level, PM induced increased ROS, which may be related to the increased lipid peroxidation, DNA damage, and apoptosis detected in PM-exposed organisms. In parallel, upregulation of the antioxidant system was detected after PM exposure, with increased superoxide dismutase, glutathione S-transferase and glutathione reductase activities, and thiol levels. The increased of Nrf2 target genes and the activation of an electrophile response element-driven reporter Tg(EPRE:LUC-EGFP) suggest that the Nrf2 pathway can mediate a fast response to PM, leading to antioxidant amplification. By using high-resolution respirometry, we found that exposure to PM decreased the oxygen consumption in all respiratory stages, disrupting the oxidative phosphorylation and inhibiting the electron transfer system, leading to decrease in bioenergetics capacity. In addition, PM led to increases of residual oxygen consumption and changes in substrate control ratio. Glucose metabolism seems to be affected by PM, with increased lactate dehydrogenase and decreased citrate synthase activities. Taken together, our results demonstrated the adverse effects of acute sublethal PM concentrations during larval development in zebrafish, causing apparent mitochondrial dysfunction, indicating a potential mechanism to redox unbalance and oxidative stress, which may be linked to the detected cell death and alterations in normal behavior patterns caused by acute PM exposure.


Interpretation of moiré phenomenon in the image domain.
We propose an interpretation of moiré phenomenon in the image domain. The interpretation is basically based on the analysis of the waveform of the line families. The period, angle, and intensity profile of moiré fringes can be obtained directly in the image domain according to this interpretation. Moreover, pseudo-moiré can be interpreted visually with the consideration of the illusional contrast of the human visual system. The interpretation, which is consistent with the Fourier theory when the two superposed gratings are periodic, involves only the image domain and shows remarkable simplicity, just like the indicial equation method.


Specificity of cone inputs to macaque retinal ganglion cells.
The specificity of cone inputs to ganglion cells has implications for the development of retinal connections and the nature of information transmitted to higher areas of the brain. We introduce a rapid and precise method for measuring signs and magnitudes of cone inputs to visual neurons. Colors of stimuli are modulated around circumferences of three color planes in clockwise and counterclockwise directions. For each neuron, the projection of the preferred vector in each plane was estimated by averaging the response phases to clockwise and counterclockwise modulation. The signs and weights of cone inputs were derived directly from the preferred vectors. The efficiency of the method enables us to measure cone inputs at different temporal frequencies and short-wavelength-sensitive (S) cone adaptation levels. The results show that S-cone inputs to the parvocellular and magnocellular ganglion cells are negligible, which implies underlying connectional specificity in the retinal circuitry.


Estimating constrained multi-fiber diffusion MR volumes by orientation clustering.
Diffusion MRI is a valuable tool for mapping tissue microstructure; however, multi-fiber models present challenges to image analysis operations. In this paper, we present a method for estimating models for such operations by clustering fiber orientations. Our approach is applied to ball-and-stick diffusion models, which include an isotropic tensor and multiple sticks encoding fiber volume and orientation. We consider operations which can be generalized to a weighted combination of fibers and present a method for representing such combinations with a mixture-of-Watsons model, learning its parameters by Expectation Maximization. We evaluate this approach with two experiments. First, we show it is effective for filtering in the presence of synthetic noise. Second, we demonstrate interpolation and averaging by construction of a tractography atlas, showing improved reconstruction of white matter pathways. These experiments indicate that our method is useful in estimating multi-fiber ball-and-stick diffusion volumes resulting from a range of image analysis operations.


A common thermal niche among geographically diverse populations of the widely distributed tree species Eucalyptus tereticornis: No evidence for adaptation to climate-of-origin.
Impacts of climate warming depend on the degree to which plants are constrained by adaptation to their climate-of-origin or exhibit broad climatic suitability. We grew cool-origin, central and warm-origin provenances of Eucalyptus tereticornis in an array of common temperature environments from 18 to 35.5°C to determine if this widely distributed tree species consists of geographically contrasting provenances with differentiated and narrow thermal niches, or if provenances share a common thermal niche. The temperature responses of photosynthesis, respiration, and growth were equivalent across the three provenances, reflecting a common thermal niche despite a 2,200 km geographic distance and 13°C difference in mean annual temperature at seed origin. The temperature dependence of growth was primarily mediated by changes in leaf area per unit plant mass, photosynthesis, and whole-plant respiration. Thermal acclimation of leaf, stem, and root respiration moderated the increase in respiration with temperature, but acclimation was constrained at high temperatures. We conclude that this species consists of provenances that are not differentiated in their thermal responses, thus rejecting our hypothesis of adaptation to climate-of-origin and suggesting a shared thermal niche. In addition, growth declines with warming above the temperature optima were driven by reductions in whole-plant leaf area and increased respiratory carbon losses. The impacts of climate warming will nonetheless vary across the geographic range of this and other such species, depending primarily on each provenance's climate position on the temperature response curves for photosynthesis, respiration, and growth.


Wide tuning range wavelength-swept laser with a single SOA at 1020 nm for ultrahigh resolution Fourier-domain optical coherence tomography.
In this study, we demonstrated a wide tuning range wavelength-swept laser with a single semiconductor optical amplifier (SOA) at 1020 nm for ultrahigh resolution, Fourier-domain optical coherence tomography (UHR, FD-OCT). The wavelength-swept laser was constructed with an external line-cavity based on a Littman configuration. An optical wavelength selection filter consisted of a grating, a telescope, and a polygon scanner. Before constructing the optical wavelength selection filter, we observed that the optical power, the spectrum bandwidth, and the center wavelength of the SOA were affected by the temperature of the thermoelectric (TE) cooler in the SOA mount as well as the applied current. Therefore, to obtain a wide wavelength tuning range, we adjusted the temperature of the TE cooler in the SOA mount. When the temperature in the TE cooler was 9 °C, our swept source had a tuning range of 142 nm and a full-width at half-maximum (FWHM) of 121.5 nm at 18 kHz. The measured instantaneous spectral bandwidth (δλ) is 0.085 nm, which was measured by an optical spectrum analyzer with a resolution bandwidth of 0.06 nm. This value corresponds to an imaging depth of 3.1 mm in air. Additionally, the averaged optical power of our swept source was 8.2 mW. In UHR, FD/SS-OCT using our swept laser, the measured axial resolution was 4.0 μm in air corresponding to 2.9 μm in tissue (n = 1.35). The sensitivity was measured to be 93.1 dB at a depth of 100 μm. Finally, we obtained retinal images (macular and optic disk) and a corneal image.


Efficacy of the protease inhibitor BI 201335, polymerase inhibitor BI 207127, and ribavirin in patients with chronic HCV infection.
Therapeutic regimens are being developed for patients with hepatitis C virus (HCV) infection that do not include the combination of peginterferon alfa and ribavirin. We investigated the antiviral effect and safety of BI 201335 (an inhibitor of the NS3/4A protease) and BI 207127 (an inhibitor of the NS5B non-nucleoside polymerase) with ribavirin. Thirty-two treatment-naïve patients with chronic HCV genotype 1 infection were randomly assigned to groups that were given 400 mg or 600 mg BI 207127 3 times daily plus 120 mg BI 201335 once daily and 1000 to 1200 mg/day ribavirin for 4 weeks. The primary efficacy end point was virologic response (HCV RNA level <25 IU/mL at week 4). Thirty-two patients received treatment; 31 completed all 4 weeks of assigned combination therapy. In the group given BI 207127 400 mg 3 times daily, the rates of virologic response were 47%, 67%, and 73% at days 15, 22, and 29; a higher rate of response was observed in patients with genotype-1b compared with genotype-1a infections. In the group given BI 207127 600 mg 3 times daily, the rates of virologic response were 82%, 100%, and 100%, respectively, and did not differ among genotypes. One patient in the group given 400 mg 3 times daily had virologic breakthrough (≥1 log(10) rebound in HCV RNA) at day 22. The most frequent adverse events were mild gastrointestinal disorders, rash, and photosensitivity. There were no severe or serious adverse events; no patients discontinued therapy prematurely. The combination of the protease inhibitor BI 201335, the polymerase inhibitor BI 207127, and ribavirin has rapid and strong activity against HCV genotype-1 and did not cause serious or severe adverse events.


circRNA_010383 Acts as a Sponge for miR-135a, and Its Downregulated Expression Contributes to Renal Fibrosis in Diabetic Nephropathy.
Diabetic nephropathy (DN), a vascular complication of diabetes, is the leading cause of death in patients with diabetes. The contribution of aberrantly expressed circular RNAs (circRNAs) to DN in vivo is poorly understood. Integrated comparative circRNA microarray profiling was used to examine the expression of circRNAs in diabetic kidney of db/db mice. We found that circRNA_010383 expression was markedly downregulated in diabetic kidneys, mesangial cells, and tubular epithelial cells cultured in high-glucose conditions. circRNA_010383 colocalized with miRNA-135a (miR-135a) and inhibited miR-135a function by directly binding to miR-135a. In vitro, the knockdown of circRNA_010383 promoted the accumulation of extracellular matrix (ECM) proteins and downregulated the expression of transient receptor potential cation channel, subfamily C, member 1 (TRPC1), which is a target protein of miR-135a. Furthermore, circRNA_010383 overexpression effectively inhibited the high-glucose-induced accumulation of ECM and increased TRPC1 levels in vitro. More importantly, the kidney target of circRNA_010383 overexpression inhibited proteinuria and renal fibrosis in db/db mice. Mechanistically, we identified that a loss of circRNA_010383 promoted proteinuria and renal fibrosis in DN by acting as a sponge for miR-135a. This study reveals that circRNA_010383 may be a novel therapeutic target for DN in the future.


Dynamic focus-tracking MEMS scanning micromirror with low actuation voltages for endoscopic imaging.
We demonstrate a 3-D scanning micromirror device that combines 2-D beam scanning with focus control in the same device using micro-electro-mechanical-systems (MEMS) technology. 2-D beam scanning is achieved with a biaxial gimbal structure and focus control is obtained with a deformable mirror membrane surface. The micromirror with 800 micrometer diameter is designed to be sufficiently compact and efficient so that it can be incorporated into an endoscopic imaging probe in the future. The design, fabrication and characterization of the device are described in this paper. Using the focus-tracking MEMS scanning mirror, we achieved an optical scanning range of >16 degrees with <40 V actuation voltage at resonance and a tunable focal length between infinity and 25 mm with <100V applied bias.


Cell-lineage regulated myogenesis for dystrophin replacement: a novel therapeutic approach for treatment of muscular dystrophy.
Duchenne muscular dystrophy (DMD) is characterized in skeletal muscle by cycles of myofiber necrosis and regeneration leading to loss of muscle fibers and replacement with fibrotic connective and adipose tissue. The ongoing activation and recruitment of muscle satellite cells for myofiber regeneration results in loss of regenerative capacity in part due to proliferative senescence. We explored a method whereby new myoblasts could be generated in dystrophic muscles by transplantation of primary fibroblasts engineered to express a micro-dystrophin/enhanced green fluorescent protein (muDys/eGFP) fusion gene together with a tamoxifen-inducible form of the myogenic regulator MyoD [MyoD-ER(T)]. Fibroblasts isolated from mdx(4cv) mice, a mouse model for DMD, were efficiently transduced with lentiviral vectors expressing muDys/eGFP and MyoD-ER(T) and underwent myogenic conversion when exposed to tamoxifen. These cells could also be induced to differentiate into muDys/eGFP-expressing myocytes and myotubes. Transplantation of transduced mdx(4cv) fibroblasts into mdx(4cv) muscles enabled tamoxifen-dependent regeneration of myofibers that express muDys. This lineage control method therefore allows replenishment of myogenic stem cells using autologous fibroblasts carrying an exogenous dystrophin gene. This strategy carries several potential advantages over conventional myoblast transplantation methods including: (i) the relative simplicity of culturing fibroblasts compared with myoblasts, (ii) a readily available cell source and ease of expansion and (iii) the ability to induce MyoD gene expression in vivo via administration of a medication. Our study provides a proof of concept for a novel gene/stem cell therapy technique and opens another potential therapeutic approach for degenerative muscle disorders.


Health status of adults with congenital adrenal hyperplasia: a cohort study of 203 patients.
No consensus exists for management of adults with congenital adrenal hyperplasia (CAH) due to a paucity of data from cohorts of meaningful size. Our objective was to establish the health status of adults with CAH. We conducted a prospective cross-sectional study of adults with CAH attending specialized endocrine centers across the United Kingdom. Participants included 203 CAH patients (199 with 21-hydroxylase deficiency): 138 women, 65 men, median age 34 (range 18-69) years. Anthropometric, metabolic, and subjective health status was evaluated. Anthropometric measurements were compared with Health Survey for England data, and psychometric data were compared with appropriate reference cohorts. Glucocorticoid treatment consisted of hydrocortisone (26%), prednisolone (43%), dexamethasone (19%), or a combination (10%), with reverse circadian administration in 41% of patients. Control of androgens was highly variable with a normal serum androstenedione found in only 36% of patients, whereas 38% had suppressed levels suggesting glucocorticoid overtreatment. In comparison with Health Survey for England participants, CAH patients were significantly shorter and had a higher body mass index, and women with classic CAH had increased diastolic blood pressure. Metabolic abnormalities were common, including obesity (41%), hypercholesterolemia (46%), insulin resistance (29%), osteopenia (40%), and osteoporosis (7%). Subjective health status was significantly impaired and fertility compromised. Currently, a minority of adult United Kingdom CAH patients appear to be under endocrine specialist care. In the patients studied, glucocorticoid replacement was generally nonphysiological, and androgen levels were poorly controlled. This was associated with an adverse metabolic profile and impaired fertility and quality of life. Improvements in the clinical management of adults with CAH are required.


Narratives of Young Men With Injecting Drug Use Histories Leaving Adult Prison.
This research focuses on an under-examined aspect of the post-release prison trajectory for a seldom-researched cohort. Narratives of the immediate days/weeks surrounding release were gathered from young men with histories of injecting drug use (IDU). Twenty-eight participants (aged 19-24) released from adult prisons in Victoria, Australia, participated in face-to-face in-depth qualitative interviews after release. Analysis of findings through the lens of a "risk environment" framework reveals how their experiences were compromised by risk factors embedded in the physical spaces and social situations they inhabited, as well as the multi-sectoral policy environments under which they were governed. A complex interplay between these factors, young men's drug use and broader issues of structural vulnerability, including institutionalization and social disadvantage, combined to limit young men's chances of "success"1 on the outside. Narratives provide evidence for interventions that transform risk environments into enabling environments, thereby promoting a more successful transition from prison to community for young men with IDU histories.


Protein microarray signature of autoantibody biomarkers for the early detection of breast cancer.
Cancer patients spontaneously generate autoantibodies (AAb) to tumor-derived proteins. To detect AAb, we have probed novel high-density custom protein microarrays (NAPPA) expressing 4988 candidate tumor antigens with sera from patients with early stage breast cancer (IBC), and bound IgG was measured. We used a three-phase serial screening approach. First, a prescreen was performed to eliminate uninformative antigens. Sera from stage I-III IBC (n = 53) and healthy women (n = 53) were screened for AAb to all 4988 protein antigens. Antigens were selected if the 95th percentile of signal of cases and controls were significantly different (p < 0.05) and if the number of cases with signals above the 95th percentile of controls was significant (p < 0.05). These 761 antigens were screened using an independent set of IBC sera (n = 51) and sera from women with benign breast disease (BBD) (n = 39). From these, 119 antigens had a partial area under the ROC curve (p < 0.05), with sensitivities ranging from 9-40% at >91% specificity. Twenty-eight of these antigens were confirmed using an independent serum cohort (n = 51 cases/38 controls, p < 0.05). Using all 28 AAb, a classifier was identified with a sensitivity of 80.8% and a specificity of 61.6% (AUC = 0.756). These are potential biomarkers for the early detection of breast cancer.


Re-establishing the merits of electrical brain stimulation.
During the past decades, direct electrical stimulation (DES) has been a key method not only in determining the organization of brain networks mediating movement, language, and cognition but also in establishing many central concepts of modern neuroscience, such as the electrical nature of neural transmission, the localization of brain functions, and the homuncular arrangement of sensorimotor areas. However, recent criticisms have questioned the utility of DES and argued that data collected with this technique may be flawed and unreliable. As with every other neuroscientific method, DES does have limitations. However, existing evidence argues strongly for its validity and usefulness by demonstrating that DES produces highly specific outcomes at well-defined anatomical sites and significantly minimizes postoperative deficits in brain-damaged patients.


Oleocanthal Inhibits Catabolic and Inflammatory Mediators in LPS-Activated Human Primary Osteoarthritis (OA) Chondrocytes Through MAPKs/NF-κB Pathways.
Oleocanthal (OC), a phenolic compound present in extra virgin olive oil (EVOO), has attracted attention since its discovery for its relevant pharmacological properties in different pathogenic processes, including inflammation. Here, we investigated the involvement of OC in LPS-activated osteoarthritis (OA) human primary chondrocytes. Human primary chondrocytes were harvested from articular cartilage samples obtained from OA patients. The effects of OC on the viability of chondrocytes were tested by MTT assay. Protein and mRNA expression of several catabolic and pro-inflammatory factors after OC treatment were measured by RT-qPCR and western blot respectively. Moreover, we analysed the NO production by Griess reaction. Finally, several pathways mediators were analysed by western blot. We demonstrated that OC did not have any cytotoxic effect. Oleocanthal inhibited NO production and strongly decreased NOS2 and COX-2 protein and mRNA expression in LPS-activated human primary OA chondrocytes. Interestingly, OC also inhibits MMP-13 and ADAMTS-5. In addition, OC downregulates several pro-inflammatory factors, such as IL-6, IL-8, CCL3, LCN2 and TNF-α induced by LPS in human primary OA chondrocytes. Finally, we demonstrated that OC exerts its effects through the MAPK/P38/NF-kB pathways. These data show that OC is able to block LPS-mediated inflammatory response and MMP-13 and ADAMTS-5 induction in human primary OA chondrocytes via MAPKs/NF-kB pathways, suggesting that OC may be a promising agent for the treatment of inflammation in cartilage and a potential molecule to prevent disease progression by inhibiting metalloproteases and aggrecanases.


Nonuniform sampled scalar diffraction calculation using nonuniform fast Fourier transform.
Scalar diffraction calculations, such as the angular spectrum method (ASM) and Fresnel diffraction, are widely used in the research fields of optics, x rays, electron beams, and ultrasonics. It is possible to accelerate the calculation using fast Fourier transform (FFT); unfortunately, acceleration of the calculation of nonuniform sampled planes is limited due to the property of the FFT that imposes uniform sampling. In addition, it gives rise to wasteful sampling data if we calculate a plane having locally low and high spatial frequencies. In this Letter, we developed nonuniform sampled ASM and Fresnel diffraction to improve the problem using the nonuniform FFT.


Anticancer activity of Yashada Bhasma (bioactive nanoparticles of zinc): A human pancreatic cancer cell line study.
Pancreatic ductal adenocarcinoma is the fourth leading cause of cancer-related mortality. Efforts to improve cancer treatment through nanotechnology are at the developmental stage, and it will be gracious if the drug with anticancer property itself is a nanoparticle. Bhasma is organomineral complexes which are bioactive nanoparticles. Yashada Bhasma (incinerated processed zinc) is widely used in Ayurveda for various diseases, and there are evidence that ZnO nanoparticles are promising antitumor agent. However, no studies have been conducted on the effectiveness of Yashada Bhasma in pancreatic cancer. Two types of test drugs, Parada Marita Yashada Bhasma (PMY) and Vanaspati Jarita Marita Yashada Bhasma (JMY), were prepared as per the guidelines of pharmaceutics of Ayurveda. Particle size analyses of Yashada Bhasma and Zeta potential study was carried out initially. Further human pancreatic cancer cell line (MIA PaCa-2) study was done using in vitro sulforhodamine B assay, keeping adriamycinas control. After 48 h of incubation, antiproliferative effects were assessed. JMY and adriamycin showed dose-dependent growth inhibition of cancer cells. Both Yashada Bhasma samples showed a cytostatic effect at this concentration. The study leads to new avenues for cancer treatment by developing such unique and highly effective bioactive nano-sized therapeutic agent.


Trauma-afflicted refugees' experiences of participating in physical activity and exercise treatment: a qualitative study based on focus group discussions.
Background: Refugees with prolonged and repeated experiences of trauma, often in combination with post-migration living difficulties, are subjected to severe levels of stress and stress-related ill health, including post-traumatic stress disorder (PTSD). Physical activity (PA) is well-established as an effective stress reliever. However, the effect of PA and exercise has received scarce attention in the context of PTSD, and particularly in the field of refugees' health. Objective: The objective of this study was to explore the experience of participation in PA and exercise as part of the treatment for trauma-afflicted refugees. Method: An explorative qualitative research design was used. Six focus group discussions were conducted with 33 female and male participants that had experience of group-based PA and exercise treatment. The gathered data was analysed by qualitative content analysis. Results: The analysis resulted in one over-arching theme reflecting the participants overall experience of PA and exercise as a process of building resilience. Participants experienced improvements in both physical and mental health domains. Increased self-awareness and self-confidence were seen as additional important benefits, and the interruption of daily stressors provided a sense of relief and recovery. The treatment group settings were experienced as becoming a vehicle for overcoming social fear and isolation, which also carried an empowering and strength-building impact over to participants' family life and social relationships. Treatment characteristics were experienced as highly supportive and often referred to as the basis of other positive experiences and perceived health benefits. Conclusions: The result of this study outlines a detailed account of trauma-afflicted refugees' experiences and preferences of PA and exercise-based treatment from a broad range of perspectives. These findings provide a starting point for future research in this field and indicate a particular need for both research and intervention development to include the real-life impact of participating in such treatments.


A physical map of chromosome 2 of Arabidopsis thaliana.
A yeast artificial chromosome (YAC) physical map of chromosome 2 of Arabidopsis thaliana has been constructed by hybridization of 69 DNA markers and 61 YAC end probes to gridded arrays of YAC clones. Thirty-four YACs in four contigs define the chromosome. Complete closure of the map was not attained because some regions of the chromosome were repetitive or were not represented in the YAC library. Based on the sizes of the YACs and their coverage of the chromosome, the length of chromosome 2 is estimated to be at least 18 Mb. These data provide the means for immediately identifying the YACs containing a genetic locus mapped on Arabidopsis chromosome 2.


Ceramide: physiological and pathophysiological aspects.
Ceramide generated in the cell membrane has been shown to be central for the induction of apoptosis by death receptors and many stress stimuli such as gamma-irradiation, UV-light or infection with pathogens. Ceramide reorganizes cell membranes and forms large ceramide-enriched membrane domains that serve the spatial and temporal organization of the cellular signalosome upon activation. Thus, ceramide-enriched membrane domains mediate clustering of CD95 and DR5 to facilitate apoptosis, and they are also critically involved in apoptosis after irradiation, UV-light and infection with Pseudomonas aeruginosa. Since ceramide-enriched membrane domains amplify signals, their function is not restricted to the induction of apoptosis and it was shown that ceramide-enriched membrane domains are also involved in internalization of pathogens and the control of cytokine release from infected epithelial cells. Recent studies support the notion that changes of the ceramide metabolism are also critically involved in human diseases, for instance neurological disorders, cancer, infectious diseases and Wilson's disease.


E-cadherin and ZEB2 modulate trophoblast cell differentiation during placental development in pigs.
It is one of the important events that trophoblast cells within the placental folds differentiate into two types that differ in cell shape during placental development in pigs. This study showed that all the trophoblast cells were of similar shape between Yorkshire and Chinese Meishan pigs on day 26 of gestation; thereafter, the trophoblast cells located at the top of the placental folds became high columnar, while those cells at the base of the placental folds were cuboidal on day 50 of gestation. Additionally, on day 95 of gestation, all the trophoblast cells in Meishan pigs became cuboidal, but the trophoblast cells located at the top of the placental folds in Yorkshire pigs still remained columnar. The membranous E-cadherin and β-catenin were strongly co-expressed by the high columnar trophoblast cells but very weakly expressed by those cuboidal cells. Consistently, the expression pattern of ZEB2, the E-cadherin repressor, was inversely correlated with that of E-cadherin in the two types of trophoblast cells in the two breeds. Furthermore, electrophoretic mobility shift assays demonstrated the binding of ZEB2 to the E-cadherin promoter in nuclear extracts from porcine placental tissue. These findings suggest a ZEB2-dependent mechanism of trophoblast cell differentiation during placental development in pigs.


Synaptic interactions underlying song-selectivity in the avian nucleus HVC revealed by dual intracellular recordings.
Stimulus-dependent synaptic interactions underlying selective sensory representations in neural circuits specialized for sensory processing and sensorimotor integration remain poorly understood. The songbird telencephalic nucleus HVC is a sensorimotor area essential to learned vocal control with one projection neuron (PN) type (HVC(RA)) innervating a song premotor pathway, another PN (HVC(X)) innervating a basal ganglia pathway essential to vocal plasticity, and interneurons (HVC(Int)). Playback of the bird's own song (BOS), but not other songs, evokes action potential bursts from both PNs, but HVC(RA) and HVC(X) display distinct BOS-evoked subthreshold responses. To characterize synaptic interactions underlying HVC's BOS-selective responses and assess stimulus-evoked changes in functional interactions between HVC neurons, we made simultaneous in vivo intracellular recordings from various HVC neuron pairs in urethan-anesthetized zebra finches. Spike-triggered averaging revealed that all HVC neuron types receive common excitation and that the onset of this excitation occurs during a narrower time window in projection neurons during BOS playback. To distinguish local from extrinsic contributions to HVC subthreshold response patterns, we inactivated the HVC local circuit with GABA or occluded inhibition in single HVC(X) cells. After either treatment, BOS-evoked responses in HVC(X) neurons became purely depolarizing and subthreshold responses of HVC(X) and HVC(RA) cells became remarkably similar to one another while retaining BOS selectivity. Therefore both PN types receive a common extrinsic source of BOS-selective excitation, and local inhibition specifically alters processing of auditory information in HVC(X) cells. In HVC, excitatory and inhibitory synaptic interactions are recruited in a stimulus-dependent fashion, affecting auditory representations of the BOS locally and in other song nuclei important to song learning and production.


The Pittsburgh Sleep Quality Index: a new instrument for psychiatric practice and research.
Despite the prevalence of sleep complaints among psychiatric patients, few questionnaires have been specifically designed to measure sleep quality in clinical populations. The Pittsburgh Sleep Quality Index (PSQI) is a self-rated questionnaire which assesses sleep quality and disturbances over a 1-month time interval. Nineteen individual items generate seven "component" scores: subjective sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disturbances, use of sleeping medication, and daytime dysfunction. The sum of scores for these seven components yields one global score. Clinical and clinimetric properties of the PSQI were assessed over an 18-month period with "good" sleepers (healthy subjects, n = 52) and "poor" sleepers (depressed patients, n = 54; sleep-disorder patients, n = 62). Acceptable measures of internal homogeneity, consistency (test-retest reliability), and validity were obtained. A global PSQI score greater than 5 yielded a diagnostic sensitivity of 89.6% and specificity of 86.5% (kappa = 0.75, p less than 0.001) in distinguishing good and poor sleepers. The clinimetric and clinical properties of the PSQI suggest its utility both in psychiatric clinical practice and research activities.


Prenatal exposure to dental amalgam in the Seychelles Child Development Nutrition Study: associations with neurodevelopmental outcomes at 9 and 30 months.
Dental amalgam is approximately 50% metallic mercury and releases mercury vapor into the oral cavity, where it is inhaled and absorbed. Maternal amalgams expose the developing fetus to mercury vapor. Mercury vapor can be toxic, but uncertainty remains whether prenatal amalgam exposure is associated with neurodevelopmental consequences in offspring. To determine if prenatal mercury vapor exposure from maternal dental amalgam is associated with adverse effects to cognition and development in children. We prospectively determined dental amalgam status in a cohort of 300 pregnant women recruited in 2001 in the Republic of Seychelles to study the risks and benefits of fish consumption. The primary exposure measure was maternal amalgam surfaces present during gestation. Maternal occlusal points were a secondary measure. Outcomes were the child's mental (MDI) and psychomotor (PDI) developmental indices of the Bayley Scales of Infant Development-II (BSID-II) administered at 9 and 30 months. Complete exposure, outcome, and covariate data were available on a subset of 242 mother-child pairs. The number of amalgam surfaces was not significantly (p>0.05) associated with either PDI or MDI scores. Similarly, secondary analysis with occlusal points showed no effect on the PDI or MDI scores for boys and girls combined. However, secondary analysis of the 9-month MDI was suggestive of an adverse association present only in girls. We found no evidence of an association between our primary exposure metric, amalgam surfaces, and neurodevelopmental endpoints. Secondary analyses using occlusal points supported these findings, but suggested the possibility of an adverse association with the MDI for girls at 9 months. Given the continued widespread use of dental amalgam, we believe additional prospective studies to clarify this issue are a priority.


The ubiquitin-editing protein A20 prevents dendritic cell activation, recognition of apoptotic cells, and systemic autoimmunity.
Dendritic cells (DCs) regulate both immunity and tolerance. Here we have shown that the ubiquitin editing enzyme A20 (Tnfaip3) determines the activation threshold of DCs, via control of canonical NF-κB activation. Tnfaip3(fl/fl)Cd11c-cre(+) mice lacking A20 in DCs demonstrated spontaneous proliferation of conventional and double-negative T cells, their conversion to interferon-γ (IFN-γ)-producing effector cells, and expansion of plasma cells. They developed ds-DNA antibodies, nephritis, the antiphospholipid syndrome, and lymphosplenomegaly-features of systemic lupus erythematosus-and extramedullary hematopoiesis. A20-deficient DCs were resistant to apoptosis, caused by increased sensitivity to CD40L and RANKL prosurvival signals and upregulation of antiapoptotic proteins Bcl-2 and Bcl-x. They captured injected apoptotic cells more efficiently, resisted the inhibitory effects of apoptotic cells, and induced self-reactive effector lymphocytes. Because genetic polymorphisms in TNFAIP3 are associated with human autoimmune disorders, these findings identify A20-mediated control of DC activation as a crucial checkpoint in the development of systemic autoimmunity.


The use of routine health facility data for micro-stratification of malaria risk in mainland Tanzania.
Current efforts to estimate the spatially diverse malaria burden in malaria-endemic countries largely involve the use of epidemiological modelling methods for describing temporal and spatial heterogeneity using sparse interpolated prevalence data from periodic cross-sectional surveys. However, more malaria-endemic countries are beginning to consider local routine data for this purpose. Nevertheless, routine information from health facilities (HFs) remains widely under-utilized despite improved data quality, including increased access to diagnostic testing and the adoption of the electronic District Health Information System (DHIS2). This paper describes the process undertaken in mainland Tanzania using routine data to develop a high-resolution, micro-stratification risk map to guide future malaria control efforts. Combinations of various routine malariometric indicators collected from 7098 HFs were assembled across 3065 wards of mainland Tanzania for the period 2017-2019. The reported council-level prevalence classification in school children aged 5-16 years (PfPR5-16) was used as a benchmark to define four malaria risk groups. These groups were subsequently used to derive cut-offs for the routine indicators by minimizing misclassifications and maximizing overall agreement. The derived-cutoffs were converted into numbered scores and summed across the three indicators to allocate wards into their overall risk stratum. Of 3065 wards, 353 were assigned to the very low strata (10.5% of the total ward population), 717 to the low strata (28.6% of the population), 525 to the moderate strata (16.2% of the population), and 1470 to the high strata (39.8% of the population). The resulting micro-stratification revealed malaria risk heterogeneity within 80 councils and identified wards that would benefit from community-level focal interventions, such as community-case management, indoor residual spraying and larviciding. The micro-stratification approach employed is simple and pragmatic, with potential to be easily adopted by the malaria programme in Tanzania. It makes use of available routine data that are rich in spatial resolution and that can be readily accessed allowing for a stratification of malaria risk below the council level. Such a framework is optimal for supporting evidence-based, decentralized malaria control planning, thereby improving the effectiveness and allocation efficiency of malaria control interventions.


Anterior Cervical Discectomy and Fusion: Practice Patterns Among Greek Spinal Surgeons.
A web-based survey was conducted among Greek spinal surgeons to outline the current practice trends in regard to the surgical management of patients undergoing anterior cervical discectomy and fusion (ACDF) for degenerative cervical spine pathology. Various practice patterns exist in the surgical management of patients undergoing anterior cervical discectomy for degenerative pathology. No consensus exists regarding the type of the employed graft, the necessity of implanting a plate, the prescription of an external orthotic device, and the length of the leave of absence in these patients. A specially designed questionnaire was used for evaluating the criteria for surgical intervention, the frequency of fusion employment, the type of the graft, the frequency of plate implantation, the employment of an external spinal orthosis (ESO), the length of the leave of absence, and the prescription of postoperative physical therapy. Physicians' demographic factors were assessed including residency and spinal fellowship training, as well as type and length in practice. Eighty responses were received. Neurosurgeons represented 70%, and orthopedic surgeons represented 30%. The majority of the participants (91.3%) considered fusion necessary. Allograft was the preferred type of graft. Neurosurgeons used a plate in 42.9% of cases, whereas orthopedic surgeons in 100%. An ESO was recommended for 87.5% of patients without plates, and in 83.3% of patients with plates. The average duration of ESO usage was 4 weeks. Physical therapy was routinely prescribed postoperatively by 75% of the neurosurgeons, and by 83.3% of the orthopedic surgeons. The majority of the participants recommended 4 weeks leave of absence. The vast majority of participants considered ACDF a better treatment option than an ACD, and preferred an allograft. The majority of them employed a plate, prescribed an ESO postoperatively, and recommended physical therapy to their patients.


Methods of isolating extracellular vesicles impact down-stream analyses of their cargoes.
Viable tumor cells actively release vesicles into the peripheral circulation and other biologic fluids, which exhibit proteins and RNAs characteristic of that cell. Our group demonstrated the presence of these extracellular vesicles of tumor origin within the peripheral circulation of cancer patients and proposed their utility for diagnosing the presence of tumors and monitoring their response to therapy in the 1970s. However, it has only been in the past 10 years that these vesicles have garnered interest based on the recognition that they serve as essential vehicles for intercellular communication, are key determinants of the immunosuppressive microenvironment observed in cancer and provide stability to tumor-derived components that can serve as diagnostic biomarkers. To date, the clinical utility of extracellular vesicles has been hampered by issues with nomenclature and methods of isolation. The term "exosomes" was introduced in 1981 to denote any nanometer-sized vesicles released outside the cell and to differentiate them from intracellular vesicles. Based on this original definition, we use "exosomes" as synonymous with "extracellular vesicles." While our original studies used ultracentrifugation to isolate these vesicles, we immediately became aware of the significant impact of the isolation method on the number, type, content and integrity of the vesicles isolated. In this review, we discuss and compare the most commonly utilized methods for purifying exosomes for post-isolation analyses. The exosomes derived from these approaches have been assessed for quantity and quality of specific RNA populations and specific marker proteins. These results suggest that, while each method purifies exosomal material, there are pros and cons of each and there are critical issues linked with centrifugation-based methods, including co-isolation of non-exosomal materials, damage to the vesicle's membrane structure and non-standardized parameters leading to qualitative and quantitative variability. The down-stream analyses of these resulting varying exosomes can yield misleading results and conclusions.