Cerebrovascular permeability changes during experimental meningitis in the rat.
Alterations in the blood-brain and blood-cerebrospinal fluid barriers occur during bacterial meningitis. Preventing barrier alterations is important as the increases in barrier permeability are thought to contribute to adverse neurological outcomes. The objective of this study was to characterize pharmacokinetically cerebrovascular permeability alterations during meningeal inflammation. 14C-Sucrose was used as a quantitative marker of cerebrovascular integrity 8 hr after induction of experimental meningitis by intracisternal injection of 0, 25 or 200 micrograms lipopolysaccharides. Serum and brain tissues were obtained after tracer dosing. 14C-Sucrose influx transfer coefficients (Kin(app)) and cerebrovascular volumes (Vbr) were calculated for each brain region. Regional Vbr values were unaffected by lipopolysaccharide pretreatment. However, statistically significant increases in 14C-sucrose K(in)(app) values were observed in various brain regions (1.6- to 3.3-fold from control; P < .05). These permeability alterations cannot be attributed to changes in the systemic pharmacokinetics of 14C-sucrose as total clearance and the volume of distribution were unaffected by lipopolysaccharide treatment. This approach can be used in future studies to examine the contribution of various inflammatory mediators to altered cerebrovascular permeabilities during experimental meningitis.


Darbepoetin alfa administration in patients with non-Hodgkin lymphoma and chemotherapy-induced anemia receiving (±R) CHOP.
IMPACT NHL was a multicenter, observational study in adults with non-Hodgkin lymphoma receiving CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone) chemotherapy with or without rituximab. Erythropoietin-stimulating agent treatment was given according to routine clinical practice and physician preference. In a subanalysis, outcomes were evaluated in 207 patients who received darbepoetin alfa (DA). The most common reason (81%) for initiating DA was low/declining hemoglobin (Hb) concentration. Mean (±standard deviation) duration of DA exposure was 8.8 ± 6.9 weeks (mean number of doses, 5.1 ± 4.6). Overall, 23% of patients had chemotherapy and DA treatment synchronized more than 75% of the time. At the time of DA initiation, 67% of patients had Hb concentrations in the guideline-recommended range (9-11 g/dl). Of 89 patients with Hb concentrations <10 g/dl at DA initiation and still receiving DA 5 weeks later, 92% (Kaplan-Meier) achieved Hb concentrations 10-12 g/dl between week 5 and at the end of treatment.


Foot and Ankle Kinematics and Dynamic Electromyography: Quantitative Analysis of Recovery From Peroneal Neuropathy in a Professional Football Player.
The assessment of neuromuscular recovery after peripheral nerve surgery has typically been a subjective physical examination. The purpose of this report was to assess the value of gait analysis in documenting recovery quantitatively. A professional football player underwent gait analysis before and after surgery for a peroneal intraneural ganglion cyst causing a left-sided foot drop. Surface electromyography (SEMG) recording from surface electrodes and motion parameter acquisition from a computerized motion capture system consisting of 10 infrared cameras were performed simultaneously. A comparison between SEMG recordings before and after surgery showed a progression from disorganized activation in the left tibialis anterior and peroneus longus muscles to temporally appropriate activation for the phase of the gait cycle. Kinematic analysis of ankle motion planes showed resolution from a complete foot drop preoperatively to phase-appropriate dorsiflexion postoperatively. Gait analysis with dynamic SEMG and motion capture complements physical examination when assessing postoperative recovery in athletes.


Prediction of Preeclampsia and Intrauterine Growth Restriction: Development of Machine Learning Models on a Prospective Cohort.
Preeclampsia and intrauterine growth restriction are placental dysfunction-related disorders (PDDs) that require a referral decision be made within a certain time period. An appropriate prediction model should be developed for these diseases. However, previous models did not demonstrate robust performances and/or they were developed from datasets with highly imbalanced classes. In this study, we developed a predictive model of PDDs by machine learning that uses features at 24-37 weeks' gestation, including maternal characteristics, uterine artery (UtA) Doppler measures, soluble fms-like tyrosine kinase receptor-1 (sFlt-1), and placental growth factor (PlGF). A public dataset was taken from a prospective cohort study that included pregnant women with PDDs (66/95, 69%) and a control group (29/95, 31%). Preliminary selection of features was based on a statistical analysis using SAS 9.4 (SAS Institute). We used Weka (Waikato Environment for Knowledge Analysis) 3.8.3 (The University of Waikato, Hamilton, NZ) to automatically select the best model using its optimization algorithm. We also manually selected the best of 23 white-box models. Models, including those from recent studies, were also compared by interval estimation of evaluation metrics. We used the Matthew correlation coefficient (MCC) as the main metric. It is not overoptimistic to evaluate the performance of a prediction model developed from a dataset with a class imbalance. Repeated 10-fold cross-validation was applied. The classification via regression model was chosen as the best model. Our model had a robust MCC (.93, 95% CI .87-1.00, vs .64, 95% CI .57-.71) and specificity (100%, 95% CI 100-100, vs 90%, 95% CI 90-90) compared to each metric of the best models from recent studies. The sensitivity of this model was not inferior (95%, 95% CI 91-100, vs 100%, 95% CI 92-100). The area under the receiver operating characteristic curve was also competitive (0.970, 95% CI 0.966-0.974, vs 0.987, 95% CI 0.980-0.994). Features in the best model were maternal weight, BMI, pulsatility index of the UtA, sFlt-1, and PlGF. The most important feature was the sFlt-1/PlGF ratio. This model used an M5P algorithm consisting of a decision tree and four linear models with different thresholds. Our study was also better than the best ones among recent studies in terms of the class balance and the size of the case class (66/95, 69%, vs 27/239, 11.3%). Our model had a robust predictive performance. It was also developed to deal with the problem of a class imbalance. In the context of clinical management, this model may improve maternal mortality and neonatal morbidity and reduce health care costs.


Mesenchymal stem cells: a new trend for cell therapy.
Mesenchymal stem cells (MSCs), the major stem cells for cell therapy, have been used in the clinic for approximately 10 years. From animal models to clinical trials, MSCs have afforded promise in the treatment of numerous diseases, mainly tissue injury and immune disorders. In this review, we summarize the recent opinions on methods, timing and cell sources for MSC administration in clinical applications, and provide an overview of mechanisms that are significant in MSC-mediated therapies. Although MSCs for cell therapy have been shown to be safe and effective, there are still challenges that need to be tackled before their wide application in the clinic.


Dispersion of Nanomaterials in Aqueous Media: Towards Protocol Optimization.
The sonication process is commonly used for de-agglomerating and dispersing nanomaterials in aqueous based media, necessary to improve homogeneity and stability of the suspension. In this study, a systematic step-wise approach is carried out to identify optimal sonication conditions in order to achieve a stable dispersion. This approach has been adopted and shown to be suitable for several nanomaterials (cerium oxide, zinc oxide, and carbon nanotubes) dispersed in deionized (DI) water. However, with any change in either the nanomaterial type or dispersing medium, there needs to be optimization of the basic protocol by adjusting various factors such as sonication time, power, and sonicator type as well as temperature rise during the process. The approach records the dispersion process in detail. This is necessary to identify the time points as well as other above-mentioned conditions during the sonication process in which there may be undesirable changes, such as damage to the particle surface thus affecting surface properties. Our goal is to offer a harmonized approach that can control the quality of the final, produced dispersion. Such a guideline is instrumental in ensuring dispersion quality repeatability in the nanoscience community, particularly in the field of nanotoxicology.


Pressor response to a postural change in cirrhosis: an experimental study in the CCl4-treated rat.
1. Systemic hypotension, blunted cardiovascular responsiveness to noradrenaline and an abnormal hypertensive pressor response to a postural change have been described in cirrhotic patients. 2. We have examined the role of blunted responsiveness in these abnormalities by studying basal arterial blood pressure and its response to a postural change (vertical head-up 90 degrees tilting) in conscious and pithed CCl4-treated (cirrhotic) rats, as well as assessing the pressor response to noradrenaline in vivo and the vascular contractile response to noradrenaline in vitro. 3. A diminished hypotensive response to a change in posture was found in pre-cirrhotic portal hypertensive rats, whereas an inverted hypertensive pressor response in the face of systemic hypotension occurred in the cirrhotic rats with portal hypertension. 4. The inverted pressor response was abolished in the pithed portal hypertensive cirrhotic rats. 5. The pressor response to noradrenaline in vivo in conscious cirrhotic rats and the vascular contractile responsiveness to noradrenaline in vitro were intact. 6. We conclude that blunted responsiveness to noradrenaline is not a contributory factor to the development of systemic hypotension or the inverted pressor response to a change in posture in cirrhosis.


The yeast KRE9 gene encodes an O glycoprotein involved in cell surface beta-glucan assembly.
The yeast KRE9 gene encodes a 30-kDa secretory pathway protein involved in the synthesis of cell wall (1-->6)-beta-glucan. Disruption of KRE9 leads to serious growth impairment and an altered cell wall containing less than 20% of the wild-type amount of (1-->6)-beta-glucan. Analysis of the glucan material remaining in a kre9 delta null mutant indicated a polymer with a reduced average molecular mass. kre9 delta null mutants also displayed several additional cell-wall-related phenotypes, including an aberrant multiply budded morphology, a mating defect, and a failure to form projections in the presence of alpha-factor. Double mutants were generated by crossing kre9 delta strains with strains harboring a null mutation in the KRE1, KRE6, or KRE11 gene, and each of these double mutants was found to be inviable in the SEY6210 background. Similar crosses with null mutations in the KRE5 and SKN1 genes indicated that these double mutants were no more severely affected than kre5 delta or kre9 delta single mutants alone. Antibodies were generated against Kre9p and detected an O glycoprotein of approximately 55 to 60 kDa found in the extracellular medium of a strain overproducing Kre9p.


A mutant Drosophila insulin receptor homolog that extends life-span and impairs neuroendocrine function.
The Drosophila melanogaster gene insulin-like receptor (InR) is homologous to mammalian insulin receptors as well as to Caenorhabditis elegans daf-2, a signal transducer regulating worm dauer formation and adult longevity. We describe a heteroallelic, hypomorphic genotype of mutant InR, which yields dwarf females with up to an 85% extension of adult longevity and dwarf males with reduced late age-specific mortality. Treatment of the long-lived InR dwarfs with a juvenile hormone analog restores life expectancy toward that of wild-type controls. We conclude that juvenile hormone deficiency, which results from InR signal pathway mutation, is sufficient to extend life-span, and that in flies, insulin-like ligands nonautonomously mediate aging through retardation of growth or activation of specific endocrine tissue.


The influence of head-of-bed elevation in patients with obstructive sleep apnea.
The purpose of this study is to test the effects of a mild degree of head-of-bed elevation (HOBE) (7.5°) on obstructive sleep apnea (OSA) severity and sleep quality. OSA patients were recruited from a single sleep clinic (Criciúma, Santa Catarina, Brazil). Following a baseline polysomnography (PSG), all patients underwent a PSG with HOBE (within 2 weeks). In addition, a subset of patients performed a third PSG without HOBE. Fifty-two patients were included in the study (age 53.2 ± 9.1 years; BMI 29.6 ± 4.8 kg/m2, neck circumference 38.9 ± 3.8 cm, and Epworth Sleepiness Scale 15 ± 7). Compared to baseline, HOBE significantly decreased the apnea-hypopnea index (AHI) from 15.7 [11.3-22.5] to 10.7 [6.6-16.5] events/h; p < 0.001 and increased minimum oxygen saturation from 83.5 [77.5-87] to 87 [81-90]%; p = 0.003. The sleep architecture at baseline and HOBE were similar. However, sleep efficiency increased slightly but significantly with HOBE (87.2 [76.7-90.7] vs 88.8 [81.6-93.3]; p = 0.005). The AHI obtained at the third PSG without HOBE (n = 7) returned to baseline values. Mild HOBE significantly improves OSA severity without interfering in sleep architecture and therefore is a simple alternative treatment to ameliorate OSA.


Granulocyte-colony stimulating factor improves Parkinson's disease associated with co-morbid depression: an experimental exploratory study.
The present study was designed to evaluate the effect of granulocyte-colony stimulating factor (G-CSF) in the treatment of Parkinson's disease (PD), the second most common neurodegenerative disease characterized by muscle and movement disorder, often associated with depression. PD is very difficult to treat. Hence, the present study was aimed to evaluate the effect of G-CSF in PD associated with depression. Adult Wistar male rats weighing about 180-250 g were selected and divided into five groups in parallel designed method namely; control group (n = 5); sham operated group (n = 5); Vehicle group (n = 5); G-CSF group (70 μg/kg, s.c.) (n = 5) and L-DOPA group (n = 5). The rats were treated with 6-hydroxydopamine (6-OHDA) on day 0 and then treatment was continued for 14 day of L-DOPA/carbidopa, whereas G-CSF (70 μg/kg, s.c.) was given from day 1 to 6. Thereafter, adhesive removal and forced swim tests were conducted to evaluate the behavioral outcome of G-CSF treatment. The finding was correlated and analyzed with Nissl staining findings for the final conclusion. The behavioral parameters were assessed and found to be ameliorate the symptoms of Parkinson's and reduced the depression like behavior in PD. The histological findings were supported the behavioral findings and showed pathological improvement. As a preliminary work, the present study first time suggested that G-CSF have a potential role in PD and associated depression.


Sarcolemmal K+ channel activity in developing rat skeletal muscle membranes.
A method has been adapted to produce membrane vesicles suitable for routine membrane patch clamping from neonate rat skeletal muscle. Single K+ channel activity was recorded from cell-free inside-out patches. Most Ca2(+)-activated voltage sensitive channels had large conductances of up to 300 pS, as determined from their current/voltage relationship, and an open probability (Po) approaching unity at positive membrane potentials. A lower conductance K+ channel, probably responsible for inward rectification, had a lower conductance of about 100 pS. Outward rectifying K+ channels were also observed with the lowest conductance, about 40 pS. 0.1 mM ATP when applied to the inner membrane surface reduced or blocked activity, drastically reducing Po without altering single channel conductance. Such an effect has been reported in other preparations but was different in the neonate preparation in that it blocked channels with conductances as high as 300 pS. The simple preparation described, which we have also used successfully on mature rat and mouse skeletal muscle, has potential in the analysis of channel activities in various conditions and pathologies without the need for tissue culture to produce suitable membrane preparations.


Time to change how we describe biodiversity.
Taxonomists are arguably the most active annotators of the natural world, collecting and publishing millions of phenotype data annually through descriptions of new taxa. By formalizing these data, preferably as they are collected, taxonomists stand to contribute a data set with research potential that rivals or even surpasses genomics. Over a decade of electronic innovation and debate has initiated a revolution in the way that the biodiversity is described. Here, we opine that a new generation of semantically based digital scaffolding, presently in various stages of completeness, and a commitment by taxonomists and their colleagues to undertake this transformation, are required to complete the taxonomic revolution and critically broaden the relevance of its products.


Manipulating attention via mindfulness induction improves P300-based brain-computer interface performance.
In this study, we examined the effects of a short mindfulness meditation induction (MMI) on the performance of a P300-based brain-computer interface (BCI) task. We expected that MMI would harness present-moment attentional resources, resulting in two positive consequences for P300-based BCI use. Specifically, we believed that MMI would facilitate increases in task accuracy and promote the production of robust P300 amplitudes. Sixteen-channel electroencephalographic data were recorded from 18 subjects using a row/column speller task paradigm. Nine subjects participated in a 6 min MMI and an additional nine subjects served as a control group. Subjects were presented with a 6 × 6 matrix of alphanumeric characters on a computer monitor. Stimuli were flashed at a stimulus onset asynchrony (SOA) of 125 ms. Calibration data were collected on 21 items without providing feedback. These data were used to derive a stepwise linear discriminate analysis classifier that was applied to an additional 14 items to evaluate accuracy. Offline performance analyses revealed that MMI subjects were significantly more accurate than control subjects. Likewise, MMI subjects produced significantly larger P300 amplitudes than control subjects at Cz and PO7. The discussion focuses on the potential attentional benefits of MMI for P300-based BCI performance.


Continued risky injection subsequent to syringe exchange use among injection drug users in New York City.
Although the vast majority of injection drug users (IDUs) attending syringe exchange programs in New York City have stopped risky injection (injecting with syringes used by someone else), there remains a subgroup of IDUs who continue to engage in high-risk injecting behaviors despite access to sterile syringes. Subjects were randomly recruited from five legally authorized syringe exchange programs in New York City between October 1992 and August 1994. Participants were asked about drug and sexual risk behavior 30 days prior to their first use of the syringe exchange as well as during the 30-day period prior to the interview while using the exchange. Of the 2,465 participants, 77.4% reported no risky injection during the 30 days prior to using syringes exchange. For this analysis we included only those who reported risky injection for the 30-day period prior to using syringe exchange (N = 556). We compared sociodemographics and behavioral characteristics of a group who continued risky injection while using the syringe exchange, "continuers," N = 158 (28.8%) with a group who reported risky injection prior to using the exchange and then ceased risky injection while using the exchange, "stoppers," N = 391(71.2%). Continuers were significantly more likely to report passing on dirty syringes to social network members and to inject cocaine at least daily. We present other predictors of continued risk and discuss the implications for interventions and make recommendations for syringe exchange programs.


The importance of blood flow volume in the brain-supplying arteries for the clinical management - the impact of collateral circulation.
An assessment of increased compensatory blood flow in the brain-supplying arteries in patients with significant carotid artery stenosis. Doppler ultrasound was performed in 218 patients over 60 years of age to evaluate both the degree of brain-supplying artery stenosis as well as the blood flow volume balance in all vessels supplying the brain: the internal carotid artery, the external carotid artery and the vertebral artery. The control group included 94 patients with no stenosis in the extracranial segments and no neurological manifestations, in whom blood flow values were calculated (the internal carotid artery - 290 mL/min, the external carotid artery - 125 mL/min, the vertebral artery - 80 mL/min); the total mean blood flow in the brain-supplying arteries was 985 mL/min. A 33% increase in blood flow was considered compensatory. In addition to the control group, 30 patients with asymptomatic stenosis of less than 50% and 12 patients after endarterectomy with mean blood flow of 920 mL/min and 960 mL/min, as well as two groups of particular interest to us, i.e. 38 patients with no compensatory blood flow increase despite significant stenosis (>50%) with mean blood flow of 844 mL/min and 44 patients with similar stenosis and with compensatory blood flow increase up to 1174 mL/min were included in the analysis. Comparison of the two groups showed several significant differences: increased blood flow (118% vs. 86% of the norm) in patients with compensated stenosis, an increased number of asymptomatic patients (70% vs. 37%) and a threefold increase in the number of patients with occlusions (15 : 5) in the group of patients with increased blood supply to the brain. All potential blood-supplying vessels, including the external carotid artery, are involved in brain tissue perfusion in some of the patients with significant stenosis. Determining the degree of compensation may have an important impact on the indications for surgical treatment, which will make a valuable contribution to the current criteria (asymptomatic/symptomatic patients).


Tolerance of baby cleansers in infants: a randomized controlled trial.
This randomized controlled trial was conducted to evaluate the tolerability of a new baby cleanser formulation Johnsons Top-to-Toe cleanser (JTT) on infantile skin. 180 healthy infants (60 in each group) were enrolled and JTT Sebamed Baby Liquid cleanser (SM), and lukewarm tap water were used on the skin of the subjects as whole body cleansers twice a week for 2 weeks. Assessment was done at baseline, 1 week and 2 weeks clinically by a dermatologist, instrumentally, and by the parents. Clinical assessment (erythema, edema, dryness and scaling); skin moisture content; skin surface pH; trans-epidermal water loss; skin oxyhemoglobin and deoxyhemoglobin; and consumer satisfaction were the outcome measures. There was no significant erythema, edema, dryness, or scaling elicited by any of the three test components. Parents did not report any side-effects. All the three studied interventions used as whole body cleansers were efficacious and well tolerated by infants.


Preservation of arterial arcades during duodenum-preserving total pancreatic head resection for intraductal papillary tumor.
Duodenum-preserving pancreatic head resection with preservation of the bile duct or without, has been performed in cases of benign or low-grade malignancies, such as intraductal papillary tumors, of the head of the pancreas. However, the selection of the patients, the area of resection in the head of the pancreas, and the operative procedures for the preservation of the pancreaticoduodenal vessels has not been realized among surgeons to apply duodenum-preserving pancreatic head resection as a radical treatment of intraductal papillary tumors. In our experience, duodenum-preserving pancreatic head resection can be applied in the majority of the patients with the branch type of intraductal papillary tumors, and it is necessary to resect completely the head of the pancreas to avoid tumor remnant and pancreatic fistula from the remaining pancreatic rim. Therefore, we modified it to include a total resection of the pancreatic head and the preservation of both anterior and posterior arterial arcades, due to the multiformity of the location of the tumor, the variation of the branch duct in the head of the pancreas, the closure of the minor papilla in some patients, and the unbalanced development of the arterial arcades of the pancreaticoduodenal region. We performed a duodenum-preserving total pancreatic head resection with preservation of the bile duct and the both anterior- and posterior-arterial arcades for 6 patients with the normal gland involving intraductal papillary tumors. The blood flow in this organ was based on the blood supply from both preserved arterial arcades, and the duodenum had retained good color, and the postoperative results were satisfactory.


Brain imaging approaches to the study of functional GI disorders: a Rome working team report.
Progresses in the understanding of human brain-gut interactions in health and disease have been limited by the lack of non-invasive techniques to study brain activity. The advent of neuroimaging techniques has made it possible not only to study the structure and function of the brain, but also to characterize signaling system underlying brain function. This article gives a brief overview of relevant functional neuroanatomy, and of the most commonly used brain imaging techniques. It summarizes published functional brain imaging studies using acute visceral stimulation of the oesophagus, stomach and colon in healthy control subjects and patients with functional GI disorders, and briefly discusses pertinent findings from these studies. The article concludes with a critical assessment of published studies, and with recommendations for improved study paradigms and analysis strategies.


Pneumonia caused by methicillin-resistant Staphylococcus aureus.
A recent increase in staphylococcal infections caused by methicillin-resistant Staphylococcus aureus (MRSA), combined with frequent, prolonged ventilatory support of an aging, often chronically ill population, has resulted in a large increase in cases of MRSA pneumonia in the health care setting. In addition, community-acquired MRSA pneumonia has become more prevalent. This type of pneumonia historically affects younger patients, follows infection with influenza virus, and is often severe, requiring hospitalization and causing the death of a significant proportion of those affected. Ultimately, hospital-acquired MRSA and community-acquired MRSA are important causes of pneumonia and present diagnostic and therapeutic challenges. Rapid institution of appropriate antibiotic therapy, including linezolid as an alternative to vancomycin, is crucial. Respiratory infection-control measures and de-escalation of initial broad-spectrum antibiotic regimens to avoid emergence of resistant organisms are also important. This article reviews the clinical features of, diagnosis of, and therapies for MRSA pneumonia.


Metabolic characterization of anaerobic fungi provides a path forward for bioprocessing of crude lignocellulose.
The conversion of lignocellulose-rich biomass to bio-based chemicals and higher order fuels remains a grand challenge, as single-microbe approaches often cannot drive both deconstruction and chemical production steps. In contrast, consortia based bioprocessing leverages the strengths of different microbes to distribute metabolic loads and achieve process synergy, product diversity, and bolster yields. Here, we describe a biphasic fermentation scheme that combines the lignocellulolytic action of anaerobic fungi isolated from large herbivores with domesticated microbes for bioproduction. When grown in batch culture, anaerobic fungi release excess sugars from both cellulose and crude biomass due to a wealth of highly expressed carbohydrate active enzymes (CAZymes), converting as much as 49% of cellulose to free glucose. This sugar-rich hydrolysate readily supports growth of Saccharomyces cerevisiae, which can be engineered to produce a range of value-added chemicals. Further, construction of metabolic pathways from transcriptomic data reveals that anaerobic fungi do not catabolize all sugars that their enzymes hydrolyze from biomass, leaving other carbohydrates such as galactose, arabinose, and mannose available as nutritional links to other microbes in their consortium. Although basal expression of CAZymes in anaerobic fungi is high, it is drastically amplified by cellobiose breakout products encountered during biomass hydrolysis. Overall, these results suggest that anaerobic fungi provide a nutritional benefit to the rumen microbiome, which can be harnessed to design synthetic microbial communities that compartmentalize biomass degradation and bioproduct formation.


Poison frog colors are honest signals of toxicity, particularly for bird predators.
Antipredator defenses and warning signals typically evolve in concert. However, the extensive variation across taxa in both these components of predator deterrence and the relationship between them are poorly understood. Here we test whether there is a predictive relationship between visual conspicuousness and toxicity levels across 10 populations of the color-polymorphic strawberry poison frog, Dendrobates pumilio. Using a mouse-based toxicity assay, we find extreme variation in toxicity between frog populations. This variation is significantly positively correlated with frog coloration brightness, a viewer-independent measure of visual conspicuousness (i.e., total reflectance flux). We also examine conspicuousness from the view of three potential predator taxa, as well as conspecific frogs, using taxon-specific visual detection models and three natural background substrates. We find very strong positive relationships between frog toxicity and conspicuousness for bird-specific perceptual models. Weaker but still positive correlations are found for crab and D. pumilio conspecific visual perception, while frog coloration as viewed by snakes is not related to toxicity. These results suggest that poison frog colors can be honest signals of prey unpalatability to predators and that birds in particular may exert selection on aposematic signal design.


Eleven year results of total hip arthroplasty in patients with secondary osteoarthritis due to slipped capital femoral epiphysis.
Total hip arthroplasty (THA) in patients with a history of Slipped Capital Femoral Epiphysis (SCFE), is typically indicated to address the consequent deformity of the proximal femur and/or acetabulum. It can be a challenging procedure for the orthopaedic surgeon. Previous studies have focused on prevention of osteoarthritis post-SCFE. However, there is a paucity of data on the outcomes of total hip arthroplasty in patients with osteoarthritis secondary to SCFE. This study was performed to assess the mid-term results of total hip arthroplasty in this patient cohort. All patients with secondary osteoarthritis due to slipped capital femoral epiphysis, treated with total hip arthroplasty between 1987 and 2005, were included in this retrospective study (n=30). Thirty patients (17 male, 13 female) met the inclusion criteria with one patient lost to follow-up and one unrelated death one year before follow up examination, thereby leaving 28 patients (32 hips) eligible for the study with a mean follow-up time period of 11.2 years. The Harris Hip Score (HHS) and MOS 36 short form health survey (SF36) were determined preoperatively and at most recent follow-up for all patients. Complications were also noted for all cases. The mean Harris Hip Score increased significantly from 47 (32-59; SD=8.3) to 92.3 (65-100; SD=8.2) (p<0.0001). The SF-36 health survey showed an improvement of quality-of-life in all sub-scales. Overall, revision surgery was required in six cases (19 %). Aseptic loosening, leading to implant removal, was noted in five cases. A single-stage revision to address infection was performed in one case. The cumulative survival rate at latest follow-up was 81 %. No other complications were encountered during the study. Despite a higher failure rate, compared to total hip arthroplasty in the treatment of primary osteoarthritis, total hip arthroplasty can be considered a feasible option for patients with secondary osteoarthritis of the hip due to slipped capital femoral epiphysis. The current study demonstrates good outcomes in patients treated with a cementless column-preserving prosthesis, which is of particular relevance for this young patient cohort. However, further clinical prospective randomized studies are warranted to provide more definitive evidence.


Addressing Family Planning Access Barriers Using an Integrated Population Health Environment Approach in Rural Uganda.
Recent studies recommend FP initiatives in rural sub-Saharan Africa operate in more context-specific ways to reduce inequities. In 2011 such a project, HoPE-LVB, was implemented by Pathfinder International and local partners among Ugandan Lake Victoria fishing communities using a Population, Health and Environment approach. Among other objectives, the project aimed to increase support for FP and women's involvement in decision-making by linking FP benefits to community needs including income generation from nature-based livelihoods. Improved FP access was measured by the project using qualitative methods and the project's indicator database in terms of five barriers: service quality, community knowledge, physical access, finances, and social acceptability. Through coordinated interventions representing multiple sectors, the project helped communities move more towards a -tipping point‖ whereby FP use has now become more an acceptable and accepted social norm. Central to this has been improving service quality and physical access as well as facilitating women's involvement in income-generation, thereby increasing their agency and contribution to decision-making including pregnancy timing.


SNP marker discovery, linkage map construction and identification of QTLs for enhanced salinity tolerance in field pea (Pisum sativum L.).
Field pea (Pisum sativum L.) is a self-pollinating, diploid, cool-season food legume. Crop production is constrained by multiple biotic and abiotic stress factors, including salinity, that cause reduced growth and yield. Recent advances in genomics have permitted the development of low-cost high-throughput genotyping systems, allowing the construction of saturated genetic linkage maps for identification of quantitative trait loci (QTLs) associated with traits of interest. Genetic markers in close linkage with the relevant genomic regions may then be implemented in varietal improvement programs. In this study, single nucleotide polymorphism (SNP) markers associated with expressed sequence tags (ESTs) were developed and used to generate comprehensive linkage maps for field pea. From a set of 36,188 variant nucleotide positions detected through in silico analysis, 768 were selected for genotyping of a recombinant inbred line (RIL) population. A total of 705 SNPs (91.7%) successfully detected segregating polymorphisms. In addition to SNPs, genomic and EST-derived simple sequence repeats (SSRs) were assigned to the genetic map in order to obtain an evenly distributed genome-wide coverage. Sequences associated with the mapped molecular markers were used for comparative genomic analysis with other legume species. Higher levels of conserved synteny were observed with the genomes of Medicago truncatula Gaertn. and chickpea (Cicer arietinum L.) than with soybean (Glycine max [L.] Merr.), Lotus japonicus L. and pigeon pea (Cajanus cajan [L.] Millsp.). Parents and RIL progeny were screened at the seedling growth stage for responses to salinity stress, imposed by addition of NaCl in the watering solution at a concentration of 18 dS m-1. Salinity-induced symptoms showed normal distribution, and the severity of the symptoms increased over time. QTLs for salinity tolerance were identified on linkage groups Ps III and VII, with flanking SNP markers suitable for selection of resistant cultivars. Comparison of sequences underpinning these SNP markers to the M. truncatula genome defined genomic regions containing candidate genes associated with saline stress tolerance. The SNP assays and associated genetic linkage maps developed in this study permitted identification of salinity tolerance QTLs and candidate genes. This constitutes an important set of tools for marker-assisted selection (MAS) programs aimed at performance enhancement of field pea cultivars.


Interaction of digitalis-like compounds with liver uptake transporters NTCP, OATP1B1, and OATP1B3.
Digitalis-like compounds (DLCs) such as digoxin, digitoxin, and ouabain, also known as cardiac glycosides, are among the oldest pharmacological treatments for heart failure. The compounds have a narrow therapeutic window, while at the same time, DLC pharmacokinetics is prone to drug-drug interactions at the transport level. Hepatic transporters organic anion transporting polypeptide (OATP) 1B1, OATP1B3, and Na(+)-dependent taurocholate co-transporting polypeptide (NTCP) influence the disposition of a variety of drugs by mediating their uptake from blood into hepatocytes. The interaction of digoxin, digitoxin, and ouabain with hepatic uptake transporters has been studied before. However, here, we systematically investigated a much wider range of structurally related DLCs for their capability to inhibit or to be transported by these transporters in order to better understand the relation between the activity and chemical structure of this compound type. We studied the uptake and inhibitory potency of a series of 14 structurally related DLCs in Chinese hamster ovary cells expressing NTCP (CHO-NTCP) and human embryonic kidney cells expressing OATP1B1 and OATP1B3 (HEK-OATP1B1 and HEK-OATP1B3). The inhibitory effect of the DLCs was measured against taurocholic acid (TCA) uptake in CHO-NTCP cells and against uptake of β-estradiol 17-β-d-glucuronide (E217βG) in HEK-OATP1B1 and HEK-OATP1B3 cells. Proscillaridin A was the most effective inhibitor of NTCP-mediated TCA transport (IC50 = 22 μM), whereas digitoxin and digitoxigenin were the most potent inhibitors of OATP1B1 and OAPTP1B3, with IC50 values of 14.2 and 36 μM, respectively. Additionally, we found that the sugar moiety and hydroxyl groups of the DLCs play different roles in their interaction with NTCP, OATP1B1, and OATP1B3. The sugar moiety decreases the inhibition of NTCP and OATP1B3 transport activity, whereas it enhances the inhibitory potency against OATP1B1. Moreover, the hydroxyl group at position 12 reinforces the inhibition of NTCP but decreases the inhibition of OATP1B1 and OATP1B3. To investigate whether DLCs can be translocated, we quantified their uptake in transporter-expressing cells by LC-MS. We demonstrated that convallatoxin, ouabain, dihydroouabain, and ouabagenin are substrates of OATP1B3. No transport was observed for the other compounds in any of the studied transporters. In summary, this work provides a step toward an improved understanding of the interaction of DLCs with three major hepatic uptake transporters. Ultimately, this can be of use in the development of DLCs that are less prone to transporter-mediated drug-drug interactions.


Clinical and Microbiological Aspects of β-Lactam Resistance in Staphylococcus lugdunensis.
Antimicrobial susceptibility results from broth microdilution MIC testing of 993 Staphylococcus lugdunensis isolates recovered from patients at a tertiary care medical center from 2008 to 2015 were reviewed. Ninety-two oxacillin-susceptible isolates were selected to assess the accuracy of penicillin MIC testing, the penicillin disk diffusion test, and three β-lactamase tests, including the cefoxitin-induced nitrocefin test, penicillin cloverleaf assay, and penicillin disk zone edge test. The results of all phenotypic tests were compared to the results of blaZ PCR. The medical records of 62 patients from whom S. lugdunensis was isolated, including 31 penicillin-susceptible and 31 penicillin-resistant strains, were retrospectively reviewed to evaluate the clinical significance of S. lugdunensis isolation, the antimicrobial agents prescribed, if any, and the clinical outcome. MIC testing revealed that 517/993 (52.1%) isolates were susceptible to penicillin and 946/993 (95.3%) were susceptible to oxacillin. The induced nitrocefin test was 100% sensitive and specific for the detection of β-lactamase compared to the blaZ PCR results, whereas the penicillin disk zone edge and cloverleaf tests showed sensitivities of 100% but specificities of only 9.1% and 89.1%, respectively. The penicillin MIC test had 100% categorical agreement with blaZ PCR, while penicillin disk diffusion yielded one major error. Only 3/31 patients with penicillin-susceptible isolates were treated with a penicillin family antimicrobial. The majority of cases were treated with other β-lactams, trimethoprim-sulfamethoxazole, or vancomycin. These data indicate that nearly all isolates of S. lugdunensis are susceptible to narrow-spectrum antimicrobial agents. Clinical laboratories in areas with resistance levels similar to those described here can help promote the use of these agents versus vancomycin by effectively designing their antimicrobial susceptibility reports to convey this message.


A Swedish survey of occupational therapists' involvement and performance in driving assessments.
The purpose of this study was to examine the extent to which occupational therapists (OTs) are involved in driving assessments in Sweden and how these assessments are performed. A questionnaire was sent to 154 geriatric, rehabilitation, and neurological clinics, and additionally directly to 19 OTs who had purchased a test battery specifically used for driving assessments. The response rate was 60%. Of those responding, 57% reported being involved in fitness-to-drive assessments. However, such assessments were carried out in various manners and diverse methods were used, ranging from unstandardized activity assessments to a test developed specifically for driving assessments. Only 19% used on-road driving tests as a complement to the clinical assessments. Apart from the lack of appropriate methods, the respondents said that they did not have sufficient knowledge to perform driving assessments and expressed a need for further education. In the future it seems necessary for OTs in Sweden to undergo specialized training and perform the assessments on a regular basis to maintain a high level of competence as driving assessors.


Survival, Pathologic Response, and Genomics in CALGB 40601 (Alliance), a Neoadjuvant Phase III Trial of Paclitaxel-Trastuzumab With or Without Lapatinib in HER2-Positive Breast Cancer.
CALGB 40601 assessed whether dual versus single human epidermal growth factor receptor 2 (HER2) -targeting drugs added to neoadjuvant chemotherapy increased pathologic complete response (pCR). Here, we report relapse-free survival (RFS), overall survival (OS), and gene expression signatures that predict pCR and survival. Three hundred five women with untreated stage II and III HER2-positive breast cancer were randomly assigned to receive weekly paclitaxel combined with trastuzumab plus lapatinib (THL), trastuzumab (TH), or lapatinib (TL). The primary end point was pCR, and secondary end points included RFS, OS, and gene expression analyses. mRNA sequencing was performed on 264 pretreatment samples. One hundred eighteen patients were randomly allocated to THL, 120 to TH, and 67 to TL. At more than 7 years of follow-up, THL had significantly better RFS and OS than did TH (RFS hazard ratio, 0.32; 95% CI, 0.14 to 0.71; P = .005; OS hazard ratio, 0.34; 95% CI, 0.12 to 0.94; P = .037), with no difference between TH and TL. Of 688 previously described gene expression signatures, significant associations were found in 215 with pCR, 45 with RFS, and only 22 with both pCR and RFS (3.2%). Specifically, eight immune signatures were significantly correlated with a higher pCR rate and better RFS. Among patients with residual disease, the immunoglobulin G signature was an independent, good prognostic factor, whereas the HER2-enriched signature, which was associated with a higher pCR rate, showed a significantly shorter RFS. In CALGB 40601, dual HER2-targeting resulted in significant RFS and OS benefits. Integration of intrinsic subtype and immune signatures allowed for the prediction of pCR and RFS, both overall and within the residual disease group. These approaches may provide means for rational escalation and de-escalation treatment strategies in HER2-positive breast cancer.


ICTV Virus Taxonomy Profile: Polycipiviridae.
Polycipiviridae is a family of picorna-like viruses with non-segmented, linear, positive-sense RNA genomes of approximately 10-12 kb. Unusually for viruses within the order Picornavirales, their genomes are polycistronic, with four (or more) consecutive 5'-proximal open reading frames (ORFs) encoding structural (and possibly other) proteins and a long 3' ORF encoding the replication polyprotein. Members of species within the family have all been detected in ants or via arthropod transcriptomic datasets. This is a summary of the International Committee on Taxonomy of Viruses (ICTV) Report on the Polycipiviridae, which is available at www.ictv.global/report/polycipiviridae.


Sexual expression in later life: a review and synthesis.
In the past decade, researchers have begun to study the sexual functioning of typical older persons. This review summarizes literature on the sexuality of men and women over age 50 as researched by social and health scientists. Research on the relationship of biological factors (changes accompanying aging), health (physical, mental, and medication use), psychological factors (attitudes, information about sex), relationship factors (status, satisfaction), and sexual functioning (desire, dysfunctions, treatment) to sexual behavior is reviewed. The review suggests that (a) men and women remain sexually active into their 70s and 80s, (b) aging-related physical changes do not necessarily lead to decline in sexual functioning, and (c) good physical and mental health, positive attitudes toward sex in later life, and access to a healthy partner are associated with continued sexual activity. In turn, regular sexual expression is associated with good physical and mental health. Progress in understanding later life sexuality requires development of comprehensive theoretical models, a broad focus on intimacy, attention to measures and samples, and research on couples. Progress in understanding is especially important, given the aging of populations.


Selection, language heritage, and the earnings trajectories of black immigrants in the United States.
Research suggests that immigrants from the English-speaking Caribbean surpass the earnings of U.S.-born blacks approximately one decade after arriving in the United States. Using data from the 1980-2000 U.S. censuses and the 2005-2007 American Community Surveys on U.S.-born black and non-Hispanic white men as well as black immigrant men from all the major sending regions of the world, I evaluate whether selective migration and language heritage of immigrants' birth countries account for the documented earnings crossover. I validate the earnings pattern of black immigrants documented in previous studies, but I also find that the earnings of most arrival cohorts of immigrants from the English-speaking Caribbean, after residing in the United States for more than 20 years, are projected to converge with or slightly overtake those of U.S.-born black internal migrants. The findings also show three arrival cohorts of black immigrants from English-speaking African countries are projected to surpass the earnings of U.S.-born black internal migrants. No arrival cohort of black immigrants is projected to surpass the earnings of U.S.-born non-Hispanic whites. Birth-region analysis shows that black immigrants from English-speaking countries experience more rapid earnings growth than immigrants from non-English-speaking countries. The arrival-cohort and birth-region variation in earnings documented in this study suggest that selective migration and language heritage of black immigrants' birth countries are important determinants of their initial earnings and earnings trajectories in the United States.


Downregulation of the ubiquitin-proteasome system in normal colonic macrophages and reinduction in inflammatory bowel disease.
In normal mucosa, intestinal lamina propria macrophages (IMACs) maintain tolerance against food antigens and the commensal bacterial flora. Several mechanisms have been identified that mediate tolerance. The ubiquitin-proteasome system (UPS) is a large multiprotein complex that degrades cellular proteins. As the UPS may modulate immune functions of IMACs, we performed a detailed investigation of UPS expression and function under normal conditions and in cells derived from patients suffering from inflammatory bowel disease (IBD). IMACs were isolated from intestinal mucosa. mRNA expression of macrophages differentiated in vitro (i.v. MACs) and IMACs was compared by Affymetrix® oligonucleotide arrays. Quantitative Taqman-PCR was performed on five exemplary proteasomal and five ubiquitinylation genes each. Proteins were analyzed by immunohistochemistry and Western blotting. Proteasome function was assessed by a fluorimetric test. Affymetrix analysis showed downregulation of mRNA expression of almost all represented proteasomal and of 22 ubiquitination-associated genes in IMACs as compared to i.v. MACs and monocytes. By quantitative PCR, up to tenfold higher mRNA expression of 10 exemplary genes of the UPS (UBE2A, UBE2D2, UBE2L6, USP14, UBB and ATPase2, β2, β5, β2i/MECL-1, β5i/LMP7) was demonstrated in i.v. MACs as compared to IMACs. Immunohistochemistry and Western blots confirmed these findings in intestinal mucosa of controls and patients suffering from diverticulitis. In contrast, a significant increase in protein amounts was found in mucosa of patients with IBD. Reduced expression of subunits of the UPS in IMACs of normal mucosa supports the concept of the presence of a nonreactive, anergic macrophage phenotype in the gut under normal conditions. Reinduction in IMACs of IBD mucosa reflects activated IMACs which can present antigenic peptides and thus support inflammation.


Cytokines, diabetes mellitus and psychopathology: a challenging combination.
The aim of this study was to investigate the association of IL-6, IL-12, and TNF-α with trait and state psychological factors in type 2 diabetic patients. Patients were divided in two groups. Group A consisted of 86 controlled diabetic patients (HbA1c<7) and the Group B consisted of 45 uncontrolled diabetic patients (HbA1c ≥ 7). During the initial phase of the study (T0), blood samples were taken for measuring IL-6, IL-12 and TNF-α serum levels as well as a battery of psychometric instruments. One year later (T1), the uncontrolled diabetic patients were re-evaluated with the use of the same psychometric instruments and with the identical blood analysis. The average values of tnf-α were significantly different among controlled (7.73 ± 5.51) and uncontrolled patients (9.29 ± 4.52) at a significance level of 5% (p=0.009). Controlled diabetic patients show a statistically significant relationship between IL-6 and neuroticism (rp=0.303, p=0.010), and between IL-12 and psychotism, (rsp=0.382, p=0.001). Controlled diabetic patients show a statistically significant relationship between IL-12 and the act out hostility (rsp=-0.307, p=0.009). The scores of the psychometric tests differ significantly between the first and second evaluation. Acting out hostility and the direction of hostility increased when HbA1c values fell below the threshold of 7, while the total hostility index, as well as all other scales, dropped when patients controlled their metabolic profile. The present results provide evidence that IL-6, IL-12 and TNF-α are closely related to the course and treatment of type 2 diabetes.


Analysis of Ewing sarcoma (EWS)-binding proteins: interaction with hnRNP M, U, and RNA-helicases p68/72 within protein-RNA complexes.
The human Ewing Sarcoma (EWS) protein belongs to the TET family of RNA-binding proteins and consists of an N-terminal transcriptional activation domain (EAD) and a C-terminal RNA-binding domain (RBD), which is extensively methylated at arginine residues. This multifunctional protein acts in transcriptional co-activation, DNA-recombination, -pairing and -repair, in splicing, and mRNA transport. The role of arginine methylation in these processes as well as the time and place of methylation within cells is still unclear. In this study, we show that methylation of recombinant EWS protein in HEK cells occurs immediately after or even during translation. Pull-down experiments with recombinant EWS protein as bait, followed by mass spectrometric analysis identified more than 30 interacting proteins independent of whether the EWS protein was methylated or not. The EWS protein interacts via its RBD with RNase-sensitive protein complexes consisting of mainly heterogeneous nuclear ribonucleoproteins (hnRNPs) and RNA helicases. HnRNP M and U, the RNA-helicases p68 and p72, but also actin and tubulin were found to interact directly with the EWS protein. Co-precipitation experiments with recombinant proteins confirmed the interaction of the EWS protein with p68 via its RBD. Colocalization of the EWS protein and the RNA-helicases in the nucleus of HEK cells was visualized by expressing labeled EWS protein and p68 or p72. When co-expressed, the labeled proteins relocated from the nucleoplasm to nucleolar capping structures. As arginine methylation within the RBD of the EWS protein are neither needed for its subcellular localization nor for its protein-protein interaction, a role of EWS protein methylation in RNA-binding and affecting the activation/repression activity or even in the stabilization of the EWS protein seems very likely.


Oculocentric frames of reference for limb movement.
We have reviewed evidence that suggests that the target for limb motion is encoded in a retinocentric frame of reference. Errors in pointing that are elicited by an illusion that distorts the perceived motion of a target are strongly correlated with errors in gaze position. The modulations in the direction and speed of ocular smooth pursuit and of the hand show remarkable similarities, even though the inertia of the arm is much larger than that of the eye. We have suggested that ocular motion is constrained so that gaze provides an appropriate target signal for the hand. Finally, ocular and manual tracking deficits in patients with cerebellar ataxia are very similar. These deficits are also consistent with the idea that a gaze signal provides the target for hand motion; in some cases limb ataxia would be a consequence of optic ataxia rather than reflecting a deficit in the control of limb motion per se. These results, as well as neurophysiological data summarized here, have led us to revise a hypothesis we have previously put forth to account for the initial stages of sensorimotor transformations underlying targeted limb motions. In the original hypothesis, target location and initial arm posture were ultimately encoded in a common frame of reference tied to somatosensation, i.e. a body-centered frame of reference, and a desired change in posture was derived from the difference between the two. In our new scheme, a movement vector is derived from the difference between variables encoded in a retinocentric frame of reference. Accordingly, gaze, with its exquisite ability to stabilize a target image even under dynamic conditions, would be used as a reference signal. Consequently, this scheme would facilitate the processing of information under conditions in which the body and the target are moving relative to each other.


Maternal Body Mass Index and Regional Anaesthesia Use at Term: Prevalence and Complications.
There is an evidence gap regarding the use of regional anaesthesia (epidural, spinal, or combined epidural/spinal anaesthesia) and associated complications by maternal body mass index (BMI). We examine associations between regional anaesthesia, mode of delivery, and regional anaesthesia complications by pre-pregnancy BMI categories among term deliveries. Retrospective cohort study of births in California, 2007-2010, utilizing linked birth certificate data and patient discharge data. Outcomes were mode of delivery (among laboured deliveries) and select regional anaesthesia complications. Multivariable Poisson regression was used to adjust for maternal characteristics. In women undergoing labour (i.e. laboured delivery), women with higher BMI categories were more likely to receive regional analgesia in a dose-response fashion (adjusted risk ratio [RR] 1.10, 95% confidence interval [CI] 1.10, 1.11 for primiparous women with category I obesity), and in those receiving regional anaesthesia, were less likely to deliver vaginally (e.g. RR 0.85, 95% CI 0.84, 0.85 for the same category of women). Regional anaesthesia complications displayed a complex relationship with maternal BMI, with women in intermediate obesity categories having decreased odds as compared to normal-weight women, and women in the highest BMI category having a twofold increased risk of complications (RR 2.34, 95% CI 1.37, 4.02 for primiparous women). Labouring women in higher BMI categories were more likely to receive regional anaesthesia and more likely to deliver via caesarean compared to normal weight women and women without regional anaesthesia. Rates of anaesthesia complications were highest among women in the highest BMI category.


Testing frequency-domain causality in multivariate time series.
We introduce a new hypothesis-testing framework, based on surrogate data generation, to assess in the frequency domain, the concept of causality among multivariate (MV) time series. The approach extends the traditional Fourier transform (FT) method for generating surrogate data in a MV process and adapts it to the specific issue of causality. It generates causal FT (CFT) surrogates with FT modulus taken from the original series, and FT phase taken from a set of series with causal interactions set to zero over the direction of interest and preserved over all other directions. Two different zero-setting procedures, acting on the parameters of a MV autoregressive (MVAR) model fitted on the original series, were used to test the null hypotheses of absence of direct causal influence (CFTd surrogates) and of full (direct and indirect) causal influence (CFTf surrogates), respectively. CFTf and CFTd surrogates were utilized in combination with the directed coherence (DC) and the partial DC (PDC) spectral causality estimators, respectively. Simulations reproducing different causality patterns in linear MVAR processes demonstrated the better accuracy of CFTf and CFTd surrogates with respect to traditional FT surrogates. Application on real MV biological data measured from healthy humans, i.e., heart period, arterial pressure, and respiration variability, as well as multichannel EEG signals, showed that CFT surrogates disclose causal patterns in accordance with expected cardiorespiratory and neurophysiological mechanisms.


The nature of the mesoderm-inducing signal in Xenopus: a transfilter induction study.
A transfilter apparatus is described, which is suitable for neutralization experiments on embryonic induction, and it is used to investigate the sensitivity of the Xenopus mesoderm-inducing signal to various inhibitors. The vegetal (inducing) tissue is placed on one side of a membrane sandwich and the animal (responding) tissue on the other side. The sandwich consists of a nylon gauze in between two Nucleopore filters and enables inhibitors in the solution to have effective access to the gap between the tissues. Control experiments show a high proportion of positive inductions of a ventral character. Using this apparatus, it is shown that the protein follistatin, which effectively inhibits activin A and B in vitro, has little or no effect on the natural signal. Likewise, antibodies to basic fibroblast growth factor, which inhibit in vitro, do not inhibit the natural signal. The two inhibitors together have a slight effect. It is concluded that neither activin nor bFGF are major components of the signal emitted by the vegetal cells of the Xenopus blastula and transmitted across the liquid gap, although they might have some other role to play in the process. Two agents of lower specificity do inhibit the transfilter induction: heparin and suramin. Suramin will also inhibit induction in animal-vegetal combinations with no intervening membranes while heparin does not. This suggests that the heparin inhibition can only occur when there is a liquid gap between the tissues, presumably because it can neutralize the signal in solution but cannot penetrate the explants themselves. The endogenous mesoderm-inducing factor(s) should therefore be sensitive to heparin in vitro.


The role of transposable element clusters in genome evolution and loss of synteny in the rice blast fungus Magnaporthe oryzae.
Transposable elements are abundant in the genomes of many filamentous fungi, and have been implicated as major contributors to genome rearrangements and as sources of genetic variation. Analyses of fungal genomes have also revealed that transposable elements are largely confined to distinct clusters within the genome. Their impact on fungal genome evolution is not well understood. Using the recently available genome sequence of the plant pathogenic fungus Magnaporthe oryzae, combined with additional bacterial artificial chromosome clone sequences, we performed a detailed analysis of the distribution of transposable elements, syntenic blocks, and other features of chromosome 7. We found significant levels of conserved synteny between chromosome 7 and the genomes of other filamentous fungi, despite more than 200 million years of divergent evolution. Transposable elements are largely restricted to three clusters located in chromosomal segments that lack conserved synteny. In contradiction to popular evolutionary models and observations from other model organism genomes, we found a positive correlation between recombination rate and the distribution of transposable element clusters on chromosome 7. In addition, the transposable element clusters are marked by more frequent gene duplications, and genes within the clusters have greater sequence diversity to orthologous genes from other fungi. Together, these data suggest that transposable elements have a profound impact on the M. oryzae genome by creating localized segments with increased rates of chromosomal rearrangements, gene duplications and gene evolution.


Comparison of feature representations in MRI-based MCI-to-AD conversion prediction.
Alzheimer's disease (AD) is a progressive neurological disorder in which the death of brain cells causes memory loss and cognitive decline. The identification of at-risk subjects yet showing no dementia symptoms but who will later convert to AD can be crucial for the effective treatment of AD. For this, Magnetic Resonance Imaging (MRI) is expected to play a crucial role. During recent years, several Machine Learning (ML) approaches to AD-conversion prediction have been proposed using different types of MRI features. However, few studies comparing these different feature representations exist, and the existing ones do not allow to make definite conclusions. We evaluated the performance of various types of MRI features for the conversion prediction: voxel-based features extracted based on voxel-based morphometry, hippocampus volumes, volumes of the entorhinal cortex, and a set of regional volumetric, surface area, and cortical thickness measures across the brain. Regional features consistently yielded the best performance over two classifiers (Support Vector Machines and Regularized Logistic Regression), and two datasets studied. However, the performance difference to other features was not statistically significant. There was a consistent trend of age correction improving the classification performance, but the improvement reached statistical significance only rarely.


Falls prevention in residential care homes: a randomised controlled trial.
to determine the effect of risk factor modification and balance exercise on falls rates in residential care homes. cluster randomised controlled trial. 196 residents (aged 60 years or over) in 20 residential care homes were enrolled (38% response rate). Homes were randomly allocated to intervention and control arms. A total of 102 residents were consigned to the intervention arm and 94 to the control arm. a multifactorial falls prevention programme including 3 months gait and balance training, medication review, podiatry and optometry. number of falls/recurrent falls per person, number of medications per person, and change in Tinetti gait and balance measure. in the intervention group there was a mean of 2.2 falls per resident per year compared with 4.0 in the control group; this failed to reach statistical significance (P = 0.2) once the intra-cluster correlation (ICC, 0.10) had been accounted for. Several risk factors were reduced in the intervention arm. falls risk factor reduction is possible in residents of care homes. A modest reduction in falls rates was demonstrated but this failed to reach statistical significance.


Single-molecule observations of topotecan-mediated TopIB activity at a unique DNA sequence.
The rate of DNA supercoil removal by human topoisomerase IB (TopIB) is slowed down by the presence of the camptothecin class of antitumor drugs. By preventing religation, these drugs also prolong the lifetime of the covalent TopIB-DNA complex. Here, we use magnetic tweezers to measure the rate of supercoil removal by drug-bound TopIB at a single DNA sequence in real time. This is accomplished by covalently linking camptothecins to a triple helix-forming oligonucleotide that binds at one location on the DNA molecule monitored. Surprisingly, we find that the DNA dynamics with the TopIB-drug interaction restricted to a single DNA sequence are indistinguishable from the dynamics observed when the TopIB-drug interaction takes place at multiple sites. Specifically, the DNA sequence does not affect the instantaneous supercoil removal rate or the degree to which camptothecins increase the lifetime of the covalent complex. Our data suggest that sequence-dependent dynamics need not to be taken into account in efforts to develop novel camptothecins.


Expression of sept3, sept5a and sept5b in the Developing and Adult Nervous System of the Zebrafish (Danio rerio).
Septins are a highly conserved family of small GTPases that form cytoskeletal filaments. Their cellular functions, especially in the nervous system, still remain largely enigmatic, but there are accumulating lines of evidence that septins play important roles in neuronal physiology and pathology. In order to further dissect septin function in the nervous system a detailed temporal resolved analysis in the genetically well tractable model vertebrate zebrafish (Danio rerio) is crucially necessary. To close this knowledge gap we here provide a reference dataset describing the expression of selected septins (sept3, sept5a and sept5b) in the zebrafish central nervous system. Strikingly, proliferation zones are devoid of expression of all three septins investigated, suggesting that they have a role in post-mitotic neural cells. Our finding that three septins are mainly expressed in non-proliferative regions was further confirmed by double-stainings with a proliferative marker. Our RNA in situ hybridization (ISH) study, detecting sept3, sept5a and sept5b mRNAs, shows that all three septins are expressed in largely overlapping regions of the developing brain. However, the expression of sept5a is much more confined compared to sept3 and sept5b. In contrast, the expression of all the three analyzed septins is largely similar in the adult brain.


Antithrombotic and thrombolytic therapy for ischemic stroke: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy.
This chapter about treatment and prevention of stroke is part of the 7th ACCP Conference on Antithrombotic and Thrombolytic Therapy: Evidence Based Guidelines. Grade 1 recommendations are strong and indicate that the benefits do, or do not, outweigh risks, burden, and costs. Grade 2 suggests that individual patients' values may lead to different choices (for a full understanding of the grading see Guyatt et al). Among the key recommendations in this chapter are the following: For patients with acute ischemic stroke (AIS), we recommend administration of i.v. tissue plasminogen activator (tPA), if treatment is initiated within 3 h of clearly defined symptom onset (Grade 1A). For patients with extensive and clearly identifiable hypodensity on CT, we recommend against thrombolytic therapy (Grade 1B). For unselected patients with AIS of > 3 h but < 6 h, we suggest clinicians not use i.v. tPA (Grade 2A). For patients with AIS, we recommend against streptokinase (Grade 1A) and suggest clinicians not use full-dose anticoagulation with i.v. or subcutaneous heparins or heparinoids (Grade 2B). For patients with AIS who are not receiving thrombolysis, we recommend early aspirin therapy, 160 to 325 mg qd (Grade 1A). For AIS patients with restricted mobility, we recommend prophylactic low-dose subcutaneous heparin or low molecular weight heparins or heparinoids (Grade 1A); and for patients who have contraindications to anticoagulants, we recommend use of intermittent pneumatic compression devices or elastic stockings (Grade 1C). In patients with acute intracerebral hematoma, we recommend the initial use of intermittent pneumatic compression (Grade 1C+). In patients with noncardioembolic stroke or transient ischemic attack (TIA) [ie, atherothrombotic, lacunar or cryptogenic], we recommend treatment with an antiplatelet agent (Grade 1A) including aspirin, 50 to 325 mg qd; the combination of aspirin and extended-release dipyridamole, 25 mg/200 mg bid; or clopidogrel, 75 mg qd. In these patients, we suggest use of the combination of aspirin and extended-release dipyridamole, 25/200 mg bid, over aspirin (Grade 2A) and clopidogrel over aspirin (Grade 2B). For patients who are allergic to aspirin, we recommend clopidogrel (Grade 1C+). In patients with atrial fibrillation and a recent stroke or TIA, we recommend long-term oral anticoagulation (target international normalized ratio, 2.5; range, 2.0 to 3.0) [Grade 1A]. In patients with venous sinus thrombosis, we recommend unfractionated heparin (Grade 1B) or low molecular weight heparin (Grade 1B) over no anticoagulant therapy during the acute phase.


Bio2RDF: towards a mashup to build bioinformatics knowledge systems.
Presently, there are numerous bioinformatics databases available on different websites. Although RDF was proposed as a standard format for the web, these databases are still available in various formats. With the increasing popularity of the semantic web technologies and the ever growing number of databases in bioinformatics, there is a pressing need to develop mashup systems to help the process of bioinformatics knowledge integration. Bio2RDF is such a system, built from rdfizer programs written in JSP, the Sesame open source triplestore technology and an OWL ontology. With Bio2RDF, documents from public bioinformatics databases such as Kegg, PDB, MGI, HGNC and several of NCBI's databases can now be made available in RDF format through a unique URL in the form of http://bio2rdf.org/namespace:id. The Bio2RDF project has successfully applied the semantic web technology to publicly available databases by creating a knowledge space of RDF documents linked together with normalized URIs and sharing a common ontology. Bio2RDF is based on a three-step approach to build mashups of bioinformatics data. The present article details this new approach and illustrates the building of a mashup used to explore the implication of four transcription factor genes in Parkinson's disease. The Bio2RDF repository can be queried at http://bio2rdf.org.


Dissemination of contact activation in plasma by plasma kallikrein.
The dissemination of contact activation of plasma was examined by measuring the cleavage of Hageman factor (HF) molecules on two separate sets of kaolin particles, one of which contained all of the components of the contact activation system, HF, prekallikrein (PK) and high molecular weight kininogen (HMWK) in whole normal plasma, and the second set of particles containing only HF and HMWK, being prepared with PK-deficient plasma. After mixing of the particles, cleavage of HF on the second set of particles occurred at a rate similar to that occurring on the first set of particles. This indicated that rapid dissemination and burst of activity of the contact reaction takes place in fluid phase. A supernatant factor, responsibel for the dissemination of the contact reaction, was identified as kallikrein. A rapid appearance of cleaved PK (kallikrein) and HMWK on both the kaolin surface and in the supernate was observed. Within 40 s, > 70-80% of the PK and HMWK in the supernate was cleaved. On the surface, approximately 70% of each radiolabeled protein was cleaved at the earliest measurement. Cleavage of PK by activated HF occurred at least 17 times faster on the surface than in the fluid phase, as virtually no cleavage of PK occurred in fluid phase. Each molecule of surface-bound, activated HF was calculated to cleave at a minimum, 20 molecules of PK per minute. It is concluded that the contact activaton of plasma may be divided into three phases: (a) the reciprocal activation of a few molecules of zymogen HF and PK on the surface, with HMWK acting as cofactor to bring these molecules into apposition; (b) the rapid release of kallikrein into the fluid phase and the continued conversion of PK to kallikrein by each surface-bound molecule of activated HF; and (c) the activation by fluid-phase kallikrein of multiple surface-bound HF molecules, and the cleavage of multiple molecules of MHWK both in fluid phase and on the surface by the soluble kallikrein. The evidence suggests that steps b and c account for a great majority of the generation of contact activation of plasma.


Structural basis for influenza virus NS1 protein block of mRNA nuclear export.
Influenza viruses antagonize key immune defence mechanisms via the virulence factor non-structural protein 1 (NS1). A key mechanism of virulence by NS1 is blocking nuclear export of host messenger RNAs, including those encoding immune factors1-3; however, the direct cellular target of NS1 and the mechanism of host mRNA export inhibition are not known. Here, we identify the target of NS1 as the mRNA export receptor complex, nuclear RNA export factor 1-nuclear transport factor 2-related export protein 1 (NXF1-NXT1), which is the principal receptor mediating docking and translocation of mRNAs through the nuclear pore complex via interactions with nucleoporins4,5. We determined the crystal structure of NS1 in complex with NXF1-NXT1 at 3.8 Å resolution. The structure reveals that NS1 prevents binding of NXF1-NXT1 to nucleoporins, thereby inhibiting mRNA export through the nuclear pore complex into the cytoplasm for translation. We demonstrate that a mutant influenza virus deficient in binding NXF1-NXT1 does not block host mRNA export and is attenuated. This attenuation is marked by the release of mRNAs encoding immune factors from the nucleus. In sum, our study uncovers the molecular basis of a major nuclear function of influenza NS1 protein that causes potent blockage of host gene expression and contributes to inhibition of host immunity.


The binding of haem and zinc in the 1.9 A X-ray structure of Escherichia coli bacterioferritin.
The crystal structure of Escherichia coli bacterioferritin has been solved to 1.9 A, and shows the symmetrical binding of a haem molecule on the local twofold axis between subunits and a pair of metal atoms bound to each subunit at the ferroxidase centre. These metals have been identified as zinc by the analysis of the structure and X-ray data and confirmed by microfocused proton-induced X-ray emission experiments. For the first time the haem has been shown to be linked to both the internal and the external environments via a cluster of waters positioned above the haem molecule.


Thioesterase enzyme families: Functions, structures, and mechanisms.
Thioesterases are enzymes that hydrolyze thioester bonds in numerous biochemical pathways, for example in fatty acid synthesis. This work reports known functions, structures, and mechanisms of updated thioesterase enzyme families, which are classified into 35 families based on sequence similarity. Each thioesterase family is based on at least one experimentally characterized enzyme, and most families have enzymes that have been crystallized and their tertiary structure resolved. Classifying thioesterases into families allows to predict tertiary structures and infer catalytic residues and mechanisms of all sequences in a family, which is particularly useful because the majority of known protein sequence have no experimental characterization. Phylogenetic analysis of experimentally characterized thioesterases that have structures with the two main structural folds reveal convergent and divergent evolution. Based on tertiary structure superimposition, catalytic residues are predicted.


Changes in household food insecurity are related to changes in BMI and diet quality among Michigan Head Start preschoolers in a sex-specific manner.
Children living in households that have recently become food insecure may be particularly vulnerable to adverse weight and dietary changes, but longitudinal studies examining these associations are lacking. Using data from 501 Head Start preschoolers from Michigan (48% male) who were followed during one school year as a part of a randomized obesity prevention trial, we examined changes in children's adiposity indices and dietary quality according to changes in household food insecurity. Household food insecurity change status was categorized as persistently food secure, became food secure, persistently food insecure, or became food insecure. Linear mixed effects models were used to estimate relative changes in BMI-for-age z scores (BAZ), triceps skinfolds-for-age z scores (TAZ), or diet quality (assessed with the 2010 Healthy Eating Index) over the school year according to food insecurity category. We found that girls from households that became food insecure over the year had a 0.21 unit higher gain in BAZ than girls from households that were persistently food secure, after adjustment for potential confounders (95% CI 0.02 to 0.39, P = 0.03). Girls from households that became food secure had improvements in dietary quality over the year compared to girls from persistently food insecure households (adjusted difference in Healthy Eating Index score change = 9.1 points; 95% CI 3.0 to 15.0; p = 0.003). There were no statistically significant associations with changes in TAZ. Among boys, there were no associations between changes in household food insecurity and changes in BAZ, TAZ, or dietary quality. In summary, we found that BMI and diet quality changes of Head Start preschool girls were correlated with short-term changes in household food insecurity. Continued research efforts should focus on identifying the most effective ways to promote the health of children in food insecure households, especially those who may have recently transitioned or are transitioning into food insecurity.


Health-related quality of life (HRQOL) in Japanese osteoporotic patients and its improvement by elcatonin treatment.
Health-related quality of life (HRQOL; "QOL" hereafter) was evaluated in Japanese osteoporotic patients using three questionnaires; the SF-36 (MOS 36-Item Short-Form Health Survey; generic, profile-type), the EQ-5D (Euro Qol-5 Dimensions; generic, preference-based), and the JOQOL (Japanese Osteoporosis Quality of Life 1999; disease-targeted). The eight subscales and two summary scores of the SF-36 were impaired in these patients even after correction for age and sex. The scores on the EQ-5D and JOQOL correlated well with the subscales of the SF-36 that represent the physical aspects of physical function and bodily pain, which suggests that physical aspects are important determinants of overall QOL status in osteoporotic patients. Although the QOL scores did not correlate with bone mineral density, they were markedly influenced by the presence of vertebral fractures. In particular, the presence of two or more vertebral fractures greatly decreased the QOL scores. We then evaluated the QOL scores before and after treatment. The patients were either given calcium supplementation alone or calcium plus once-weekly elcatonin (Elcitonin, Asahi Kasei Pharma, Tokyo, Japan) injection. Elcatonin treatment markedly improved diverse aspects of the QOL, whereas calcium alone did not. The current data suggest that osteoporosis, especially in the presence of vertebral fracture, is associated with compromised QOL, and therapeutic intervention for osteoporosis should be evaluated in terms of QOL, as well as in terms of increases in bone mineral density and fracture prevention.


Glyphosate resistance in Echinochloa colona: phenotypic characterisation and quantification of selection intensity.
A population of Echinochloa colona infesting agricultural fields in the northern region of Western Australia evolved glyphosate resistance after 10 years of glyphosate selection. This study identified two phenotypic (susceptible S versus resistant R) lines from within a segregating glyphosate-resistant population. Estimation of survival, growth and reproductive rates of the phenotypes in response to glyphosate selection helped to characterise the level of resistance, fitness and the selection intensity for glyphosate in this species. Estimations of LD(50) (lethal dose) and GR(50) (growth rate) showed an eightfold glyphosate resistance in this population. The resistant index based on the estimation of seed number (SY(n50)) showed a 13-fold resistance. As a result of linear combination of plant survival and fecundity rates, plant fitness values of 0.2 and 0.8 were estimated for the S and R phenotypes when exposed to the low dose of 270 g glyphosate ha(-1). At the recommended dose of 540 g glyphosate ha(-1) , fitness significantly decreased (fivefold) in S plants but remained markedly similar (0.7) in plants of the R phenotype. Thus, the calculated selection intensity (SI) at 540 g glyphosate ha(-1) was much greater (SI = 17) than at 270 g glyphosate ha(-1) (SI = 4). The assessment of plant survival and fecundity in response to glyphosate selection in the S and R phenotypes allowed a greater accuracy in the estimation of population fitness of both phenotypes and thus of glyphosate selection intensity in E. colona. The estimation of seed number or mass of phenotypes under herbicide selection is a true ecological measure of resistance with implications for herbicide resistance evolution.


Estimating levels of HIV testing, HIV prevention coverage, HIV knowledge, and condom use among men who have sex with men (MSM) in low-income and middle-income countries.
HIV prevalence data suggest that men who have sex with men (MSM) in low-income and middle-income countries (LMIC) are at increased risk of HIV. The aim of this article is to present global estimates on key HIV prevention needs and responses among MSM in LMIC. Data on HIV testing, HIV prevention coverage, HIV knowledge and condom use among MSM were derived from UNGASS country progress reports submitted in 2008. Eligible country estimates were used to calculate global and regional estimates, weighted for the size of MSM populations. Of 147 LMIC, 45% reported at least 1 indicator that reflects the HIV prevention needs and responses in MSM. Global weighted estimates indicate that on average 31% of MSM in LMIC were tested for HIV; 33% were reached by HIV prevention programs; 44% had correct HIV knowledge; and 54% used condoms the last time they had anal sex with a man. The 2008 UNGASS country reports represent the largest harmonized data set to date of HIV prevention needs and responses among MSM in LMIC. Although reporting is incomplete and does not always conform to requirements, findings confirm that, in many LMIC, HIV prevention responses in MSM need substantial strengthening.


Influence of ovarian hormones on urogenital infection.
Numerous studies have examined the influence of hormones on infectious diseases and there is now a wealth of data relating to the more specific effect of the sex hormones, oestrogen and progesterone, on urogenital infections. The interaction between these hormones and the immune system is complex and the variation of hormonal effect between species further complicates the true picture as related to humans. Although it is difficult therefore to draw general conclusions regarding predominant effects of specific hormones, there is the suggestion that oestrogen enhances the pathogenicity of many urogenital micro-organisms. Our understanding of the influential role played by sex hormones in disease pathogenesis is at an early stage and illustrates well the importance of drawing together and interpreting as a whole both epidemiological and molecular studies.


Multicentre appraisal of amyotrophic lateral sclerosis biofluid biomarkers shows primacy of blood neurofilament light chain.
The routine clinical integration of individualized objective markers of disease activity in those diagnosed with the neurodegenerative disorder amyotrophic lateral sclerosis is a key requirement for therapeutic development. A large, multicentre, clinic-based, longitudinal cohort was used to systematically appraise the leading candidate biofluid biomarkers in the stratification and potential therapeutic assessment of those with amyotrophic lateral sclerosis. Incident patients diagnosed with amyotrophic lateral sclerosis (n = 258), other neurological diseases (n = 80) and healthy control participants (n = 101), were recruited and followed at intervals of 3-6 months for up to 30 months. Cerebrospinal fluid neurofilament light chain and chitotriosidase 1 and blood neurofilament light chain, creatine kinase, ferritin, complement C3 and C4 and C-reactive protein were measured. Blood neurofilament light chain, creatine kinase, serum ferritin, C3 and cerebrospinal fluid neurofilament light chain and chitotriosidase 1 were all significantly elevated in amyotrophic lateral sclerosis patients. First-visit plasma neurofilament light chain level was additionally strongly associated with survival (hazard ratio for one standard deviation increase in log10 plasma neurofilament light chain 2.99, 95% confidence interval 1.65-5.41, P = 0.016) and rate of disability progression, independent of other prognostic factors. A small increase in level was noted within the first 12 months after reported symptom onset (slope 0.031 log10 units per month, 95% confidence interval 0.012-0.049, P = 0.006). Modelling the inclusion of plasma neurofilament light chain as a therapeutic trial outcome measure demonstrated that a significant reduction in sample size and earlier detection of disease-slowing is possible, compared with using the revised Amyotrophic Lateral Sclerosis Functional Rating Scale. This study provides strong evidence that blood neurofilament light chain levels outperform conventional measures of disease activity at the group level. The application of blood neurofilament light chain has the potential to radically reduce the duration and cost of therapeutic trials. It might also offer a first step towards the goal of more personalized objective disease activity monitoring for those living with amyotrophic lateral sclerosis.


Direct-Write X-ray Nanopatterning: A Proof of Concept Josephson Device on Bi2Sr2CaCu2O8+δ Superconducting Oxide.
We describe the first use of a novel photoresist-free X-ray nanopatterning technique to fabricate an electronic device. We have produced a proof-of-concept device consisting of a few Josephson junctions by irradiating microcrystals of the Bi2Sr2CaCu2O8+δ (Bi-2212) superconducting oxide with a 17.6 keV synchrotron nanobeam. Fully functional devices have been obtained by locally turning the material into a nonsuperconducting state by means of hard X-ray exposure. Nano-XRD patterns reveal that the crystallinity is substantially preserved in the irradiated areas that there is no evidence of macroscopic crystal disruption. Indications are that O ions have been removed from the crystals, which could make this technique interesting also for other oxide materials. Direct-write X-ray nanopatterning represents a promising fabrication method exploiting material/material rather than vacuum/material interfaces, with the potential for nanometric resolution, improved mechanical stability, enhanced depth of patterning, and absence of chemical contamination with respect to traditional lithographic techniques.


Infantile tremor syndrome secondary to peroral vitamin B12 replacement therapy: a report of two cases with myoclonus.
Abnormal movements such as tremors and myoclonus may be observed during both treatment and deficiency of vitamin B12, particularly in infants. Infantile tremor syndrome (ITS) is defined by the tetrad of pallor, developmental delay/regression, skin pigmentation, and brown scanty scalp hair. In this report, two cases with ITS aged less than one year who had myoclonic movements during vitamin peroral B12 treatment are discussed based on hematologic, neurological, and magnetic resonance images (MRI) findings, one of whom developed a whole-body tremor and rhythmic myoclonic movements, titubation, and restlessness in the hands and feet as well as diffuse cerebral atrophy on brain MRI. The infants of mothers with nutritional vitamin B12 deficiency may develop sudden abnormal movements following peroral vitamin B12 therapy and that the differential diagnosis of these disorders is highly important for the prevention of long-term neurological sequela by treatment.


Conserved rules govern genetic interaction degree across species.
Synthetic genetic interactions have recently been mapped on a genome scale in the budding yeast Saccharomyces cerevisiae, providing a functional view of the central processes of eukaryotic life. Currently, comprehensive genetic interaction networks have not been determined for other species, and we therefore sought to model conserved aspects of genetic interaction networks in order to enable the transfer of knowledge between species. Using a combination of physiological and evolutionary properties of genes, we built models that successfully predicted the genetic interaction degree of S. cerevisiae genes. Importantly, a model trained on S. cerevisiae gene features and degree also accurately predicted interaction degree in the fission yeast Schizosaccharomyces pombe, suggesting that many of the predictive relationships discovered in S. cerevisiae also hold in this evolutionarily distant yeast. In both species, high single mutant fitness defect, protein disorder, pleiotropy, protein-protein interaction network degree, and low expression variation were significantly predictive of genetic interaction degree. A comparison of the predicted genetic interaction degrees of S. pombe genes to the degrees of S. cerevisiae orthologs revealed functional rewiring of specific biological processes that distinguish these two species. Finally, predicted differences in genetic interaction degree were independently supported by differences in co-expression relationships of the two species. Our findings show that there are common relationships between gene properties and genetic interaction network topology in two evolutionarily distant species. This conservation allows use of the extensively mapped S. cerevisiae genetic interaction network as an orthology-independent reference to guide the study of more complex species.


Community treatment of severely mentally ill offenders under the jurisdiction of the criminal justice system: a review.
Very large numbers of severely mentally ill persons now fall under the jurisdiction of the criminal justice system. A number of conditions are placed on those who are returned to the community, including specific ones related to treatment. This paper reviews the principles and practice of forensic outpatient mental health treatment. MEDLINE, Psychological Abstracts, and the Index to Legal Periodicals and Books were searched from 1978, and all pertinent references were obtained. Community treatment of severely mentally ill offenders who fall under the jurisdiction of the criminal justice system has important differences from treatment of nonoffenders, which focuses on alleviation of symptoms. Patients must comply with legal restrictions on their behavior, and treatment first addresses a patient's risk of harm to the community. Mentally ill offenders are often resistant to treatment. The mental health system may be disinclined to treat them due to their resistance and their criminal history, especially a history of violence. It is critical to identify a treatment philosophy that strikes a balance between individual rights and public safety and includes clear treatment goals, a close liaison between treatment staff and the criminal justice system, adequate structure and supervision, treatment staff who are comfortable with using authority, interventions for managing violence, incorporation of the principles of case management, appropriate and supportive living arrangements, and a recognition of the role of family members and significant others in treatment.


Host-specific assembly of sponge-associated prokaryotes at high taxonomic ranks.
Sponges (Porifera) are abundant and diverse members of benthic filter feeding communities in most marine ecosystems, from the deep sea to tropical reefs. A characteristic feature is the associated dense and diverse prokaryotic community present within the sponge mesohyl. Previous molecular genetic studies revealed the importance of host identity for the community composition of the sponge-associated microbiota. However, little is known whether sponge host-specific prokaryotic community patterns observed at 97% 16S rRNA gene sequence similarity are consistent at high taxonomic ranks (from genus to phylum level). In the present study, we investigated the prokaryotic community structure and variation of 24 sponge specimens (seven taxa) and three seawater samples from Sweden. Results show that the resemblance of prokaryotic communities at different taxonomic ranks is consistent with patterns present at 97% operational taxonomic unit level.


The impact of competitive flow on distal coronary flow and on graft flow during coronary artery bypass surgery.
To determine the impact of left anterior descending-competitive flow (LAD-CF) on distal coronary flow (LAD-DF) and on left internal mammary artery-graft flow (LIMA-GF), we performed a quantitative blood-flow analysis in a swine model of a LIMA-to-LAD coronary artery bypass graft (CABG). In six swine, a LIMA-to-LAD CABG was performed. LAD blood-flow was measured bilaterally to the LIMA-to-LAD anastomosis, in the LIMA and in the pulmonary artery (cardiac output, CO) along with the LIMA pulsatility index (LIMA-PI) and the left ventricular pressure (LVP). PreCABG measurements were followed by postCABG measurements at five levels of LAD-CF: 100%, 75%, 50%, 25% and 0% after gradually snaring down a snare placed proximally of the LAD-CF flow-probe. PreCABG CO and LVP remained unchanged postCABG. LAD-DF was reduced significantly postCABG (-33%, P<0.0001). Reduction of the LAD-CF (at 75%, 50%, 25% and 0%) resulted in significant increase of LIMA-GF (+38%, +63%, +113%, +225%, P<0.036 at all LAD-CF levels), reduced PI (6.8, 5.7, 4.1, 3.1, 2.5) with simultaneous increase of LAD-DF (+8%, P=NS, +8%, P=NS, +17%, P=NS, +50%, P=0.0044). Decreased LAD-CF resulted in increased LAD-DF, increased LIMA-GF and decreased LIMA-PI. To the best of our knowledge, this is the first study where blood-flow was directly and simultaneously measured in all the components of the LIMA-to-LAD anastomosis.