Molecular characterization of hepatitis A virus isolated from acute infections in Turkey.
Hepatitis A virus is a global public health problem, especially in developing countries, and the most common cause of hepatitis in childhood. Hepatitis A virus is a single- stranded positive RNA virus subdivided to 6 genotypes (3 human,3 simian). The aim of this study was to determine the prevalent genotype in Turkey using sera of acute hepatitis A virus-infected patients from different geographical regions of the country. Sera of 137 patients with acute hepatitis A virus from different geographical regions were collected for phylogenetic analysis. The VP1-2A region of the hepatitis A virus genome was amplified by real-time-polymerase chain reaction in 76 patients where possible. Amplified polymerase chain reaction fragments were sequenced, and phylogenetic analysis was done together with other reference hepatitis A virus sequences obtained from GenBank database. Sequencing and phylogenetic analysis of the VP1-2A junction of hepatitis A virus showed that the most prevalent genotype in Turkey is IB (100%). Comparison of Turkish isolates and reference sequences of genotype IB showed a similarity of 94.9%. The same comparison was done between Turkish isolates and reference hepatitis A virus genotype IB and HM175, and it was found that similarity between them ranged from 93.0-95.9%. When Turkish isolates were compared according to Mean Percentage Nucleotide Distance analysis, similarity ranged between 95.3%-100%. Phylogenetic analysis pointed out that all Turkish isolates belong to genotype IB. Sequence analysis is a useful tool in revealing hepatitis A outbreaks, and allows us to detect and distinguish the presence of epidemic and small outbreaks.


Artificial rheotaxis.
Motility is a basic feature of living microorganisms, and how it works is often determined by environmental cues. Recent efforts have focused on developing artificial systems that can mimic microorganisms, in particular their self-propulsion. We report on the design and characterization of synthetic self-propelled particles that migrate upstream, known as positive rheotaxis. This phenomenon results from a purely physical mechanism involving the interplay between the polarity of the particles and their alignment by a viscous torque. We show quantitative agreement between experimental data and a simple model of an overdamped Brownian pendulum. The model notably predicts the existence of a stagnation point in a diverging flow. We take advantage of this property to demonstrate that our active particles can sense and predictably organize in an imposed flow. Our colloidal system represents an important step toward the realization of biomimetic microsystems with the ability to sense and respond to environmental changes.


Adverse maternal and perinatal outcomes in adolescent pregnancies: The Global Network's Maternal Newborn Health Registry study.
Adolescent girls between 15 and 19 years give birth to around 16 million babies each year, around 11% of births worldwide. We sought to determine whether adolescent mothers are at higher risk of maternal and perinatal adverse outcomes compared with mothers aged 20-24 years in a prospective, population-based observational study of newborn outcomes in low resource settings. We undertook a prospective, population-based multi-country research study of all pregnant women in defined geographic areas across 7 sites in six low-middle income countries (Kenya, Zambia, India, Pakistan, Guatemala and Argentina). The study population for this analysis was restricted to women aged 24 years or less, who gave birth to infants of at least 20 weeks' gestation and 500g or more. We compared adverse pregnancy maternal and perinatal outcomes among pregnant adolescents 15-19 years, <15 years, and adults 20-24 years. A total of 269,273 women were enrolled from January 2010 to December 2013. Of all pregnancies 11.9% (32,097/269,273) were in adolescents 15-19 years, while 0.14% (370/269,273) occurred among girls <15 years. Pregnancy among adolescents 15-19 years ranged from 2% in Pakistan to 26% in Argentina, and adolescent pregnancies <15 year were only observed in sub-Saharan Africa and Latin America. Compared to adults, adolescents did not show increased risk of maternal adverse outcomes. Risks of preterm birth and LBW were significantly higher among both early and older adolescents, with the highest risks observed in the <15 years group. Neonatal and perinatal mortality followed a similar trend in sub-Saharan Africa and Latin America, with the highest risk in early adolescents, although the differences in this age group were not significant. However, in South Asia the risks of neonatal and perinatal death were not different among adolescents 15-19 years compared to adults. This study suggests that pregnancy among adolescents is not associated with worse maternal outcomes, but is associated with worse perinatal outcomes, particularly in younger adolescents. However, this may not be the case in regions like South Asia where there are decreasing rates of adolescent pregnancies, concentrated among older adolescents. The increased risks observed among adolescents seems more likely to be associated with biological immaturity, than with socio-economic factors, inadequate antenatal or delivery care. NCT01073475.


Basophil-derived IL-4 promotes cutaneous Staphylococcus aureus infection.
Superficial cutaneous Staphylococcus aureus (S. aureus) infection in humans can lead to soft tissue infection, an important cause of morbidity and mortality. IL-17A production by skin TCRγδ+ cells in response to IL-1 and IL-23 produced by epithelial and immune cells is important for restraining S. aureus skin infection. How S. aureus evades this cutaneous innate immune response to establish infection is not clear. Here we show that mechanical injury of mouse skin by tape stripping predisposed mice to superficial skin infection with S. aureus. Topical application of S. aureus to tape-stripped skin caused cutaneous influx of basophils and increased Il4 expression. This basophil-derived IL-4 inhibited cutaneous IL-17A production by TCRγδ+ cells and promoted S. aureus infection of tape-stripped skin. We demonstrate that IL-4 acted on multiple checkpoints that suppress the cutaneous IL-17A response. It reduced Il1 and Il23 expression by keratinocytes, inhibited IL-1+IL-23-driven IL-17A production by TCRγδ+ cells, and impaired IL-17A-driven induction of neutrophil-attracting chemokines by keratinocytes. IL-4 receptor blockade is shown to promote Il17a expression and enhance bacterial clearance in tape-stripped mouse skin exposed to S. aureus, suggesting that it could serve as a therapeutic approach to prevent skin and soft tissue infection.


Epidermolysis bullosa and dental developmental age.
The dental development of permanent mandibular teeth in a small group of children with dystrophic epidermolysis bullosa (DEB) was assessed from radiographs and compared to a healthy, age-and-sex-matched control group. This was a retrospective radiographic cross-sectional study. The sample consisted of a group of 44 children aged between 4 and 15 years with DEB and healthy, age-and-sex-matched controls. Two quantitative methods of assessing tooth formation were used: (1) a combination of information about tooth length and apex width; and (2) the use of tooth length to predict age. Panoramic radiographs were digitized in order to determine tooth length and apex width. Dental age was calculated, and the difference with real age was tested with Student's t-test. The dentition of both the DEB and control groups was slightly delayed. Using the first method, the delay was 0.34 +/- 0.87 years for the DEB group and 0.29 +/- 0.97 years for the control group. Using the second method, the delay was 0.49 +/- 1.18 years for the DEB group and 0.23 +/- 0.62 years for the control group. This delay was not statistically significant for either method. The dental formation of permanent mandibular teeth in the group of children with DEB was not significantly different to that found in the control group.


Blood gases, biochemistry, and hematology of Galapagos green turtles (Chelonia mydas).
The green turtle, Chelonia mydas, is an endangered marine chelonian with a circum-global distribution. Reference blood parameter intervals have been published for some chelonian species, but baseline hematology, biochemical, and blood gas values are lacking from the Galapagos sea turtles. Analyses were done on blood samples drawn from 28 green turtles captured in two foraging locations on San Cristóbal Island (14 from each site). Of these turtles, 20 were immature and of unknown sex; the other eight were males (five mature, three immature). A portable blood analyzer (iSTAT) was used to obtain near immediate field results for pH, lactate, pO2, pCO2, HCO3-, Hct, Hb, Na, K, iCa, and Glu. Parameter values affected by temperature were corrected in two ways: (1) with standard formulas; and (2) with auto-corrections made by the iSTAT. The two methods yielded clinically equivalent results. Standard laboratory hematology techniques were employed for the red and white blood cell counts and the hematocrit determination, which was also compared to the hematocrit values generated by the iSTAT. Of all blood analytes, only lactate concentrations were positively correlated with body size. All other values showed no significant difference between the two sample locations nor were they correlated with body size or internal temperature. For hematocrit count, the iSTAT blood analyzer yielded results indistinguishable from those obtained with high-speed centrifugation. The values reported in this study provide baseline data that may be useful in comparisons among populations and in detecting changes in health status among Galapagos sea turtles. The findings might also be helpful in future efforts to demonstrate associations between specific biochemical parameters and disease.


[A case of gangliocytic paraganglioma in duodenum].
Duodenal gangliocytic paraganglioma derived from neural crest is a peculiar neuroendocrine tumor. It is incidentally found during radiographic studies or due to gastrointestinal hemorrhage caused by frequent ulceration of the overlying mucosa. Most lesions are pedunculated and submucosal with distinctive histology consisting of endocrine cells, ganglion cells and spindle-shaped Schwann cells. We experienced a duodenal gangliocytic paraganglioma in a 40-year-old woman presenting with episodes of melena. Esophagogastroduodenoscopy revealed a submucosal ulcerated tumor in the second portion of duodenum and a biopsy confirmed gangliocytic paraganglioma. The tumor was enucleated through a duodenotomy. It's size was 5.5 X 3 X 1.5 cm sized and revealed positive cellular reaction for chromogranin, synaptophysin, neuron-specific enolase, and neurofilament by immunohistochemistry. The majority of the reported duodenal gangliocytic paraganglioma were of benign nature. Therefore, radical surgery or a lymph node dissection could be avoided if that disease was confirmed. However, thorough investigation for lymph node metastasis and postoperative follow-up are needed. We report the first case of a duodenal gangliocytic paraganglioma in Korea with a review of literature.


oPOSSUM: integrated tools for analysis of regulatory motif over-representation.
The identification of over-represented transcription factor binding sites from sets of co-expressed genes provides insights into the mechanisms of regulation for diverse biological contexts. oPOSSUM, an internet-based system for such studies of regulation, has been improved and expanded in this new release. New features include a worm-specific version for investigating binding sites conserved between Caenorhabditis elegans and C. briggsae, as well as a yeast-specific version for the analysis of co-expressed sets of Saccharomyces cerevisiae genes. The human and mouse applications feature improvements in ortholog mapping, sequence alignments and the delineation of multiple alternative promoters. oPOSSUM2, introduced for the analysis of over-represented combinations of motifs in human and mouse genes, has been integrated with the original oPOSSUM system. Analysis using user-defined background gene sets is now supported. The transcription factor binding site models have been updated to include new profiles from the JASPAR database. oPOSSUM is available at http://www.cisreg.ca/oPOSSUM/


Diets Rich in Fruits and Vegetables Are Associated with Lower Cardiovascular Disease Risk in Adolescents.
Obesity and cardiovascular disease (CVD) risk are public health concerns in adolescents, yet few studies have examined the association of their diet to CVD risk factors. This study investigated associations between diet, body mass index (BMI), waist circumference (WC), blood pressure (BP), and blood lipids in 163 16-17 year olds. Diet recall data were converted into Healthy Eating Index-2010 (HEI) to assess diet quality. Differences in diet between groups with normal or obese BMI, normal or hypertensive BP, and normal or altered lipids were determined. Associations between diet and BMI, WC, BP, and lipids, controlling for race, gender, and socioeconomic status, were examined. Mean HEI was 49.2 (±12.0), with no differences observed between groups. HEI was not associated with any CVD risk. Sweetened beverage consumption was higher in obese adolescents, and positively related to total cholesterol (TC). Fruit intake was negatively related to BMI and diastolic BP. Total vegetable intake was negatively related to systolic BP. Greens and beans were negatively related to TC and LDL. Whole grains were negatively related to HDL. This research suggests a cardioprotective effect of diets rich in fruits and vegetables, as well as low in sweetened beverages in adolescents.


Cancer patients' intentions towards receiving unsolicited genetic information obtained using next-generation sequencing.
Next-generation sequencing (NGS) can be used to generate information about a patient's tumour and personal genome. This powerful diagnostic tool provides solicited and unsolicited hereditary genetic (risk) information that could have consequences for cancer patients and their quality of life. A well-defined approach for returning appropriate genetic risk information is needed in personalized cancer care. A qualitative design with semi-structured interviews was used. We conducted interviews with 24 Dutch patients with different types of cancer, both NGS-experienced and NGS-inexperienced, to learn their intentions, needs and preferences towards receiving unsolicited genetic information obtained using NGS. Almost all participants had a positive attitude towards receiving unsolicited findings. After receiving comprehensive background information on NGS, including a binning model of four categories of unsolicited findings, most participants preferred to receive only subsets of genetic information. Their main concern was their own and others' (including family members) ability to cope with (the increased risk of having) a genetic disorder. Providing background information gave cancer patients the opportunity to select subsets of findings and increased their ability to make an informed choice. Special attention is needed for social and emotional factors to support the patients themselves and when communicating test results with their family members.


nPIV velocity measurement of nanofluids in the near-wall region of a microchannel.
Colloidal suspensions of nano-sized particles in a base fluid, nanofluids, have recently gained popularity as cooling fluids mainly due to their enhanced heat transfer capabilities. However, there is controversy in the literature on the reported properties of nanofluids and their applicability, especially since there is no fundamental understanding that explains these enhancements. A better understanding of these fluids and how they interact with a solid boundary may be achieved by a detailed near-wall fluid flow study at nanoscale. This work presents for the first time the near-wall velocity measurements for nanofluids using nanoparticle image velocimetry. This novel technique uses evanescent illumination in the solid-fluid interface to measure near-wall velocity field with an out-of-plane resolution on the order of O(100 nm). Nanofluids of different concentrations were prepared by dispersing silicon dioxide particles (10 to 20 nm) in water as the base fluid. Initially, viscosity measurements were conducted for the prepared nanofluids. The near-wall velocity data were then measured and compared with that of the base fluid at the same flow condition. It was observed that even though nanofluid viscosity had increased with particle loading, the near-wall velocity values were similar to that of the base fluid for a given flow rate. Together, these measurements vindicate the homogenous and Newtonian characteristics of the nanofluids in the near-wall region. Despite the low particle concentrations investigated, the present work also discusses the complexity involved in utilizing the methodology and possible errors arising during experimentation so as to implement this measurement tool more effectively in the future.


Transplantation for polycystic kidney disease.
During the 4-year period from June 1977 to May 1981, a total of 108 patients with polycystic kidney disease and 2440 nonpolycystic patients received cadaver renal allografts in the Southeastern Organ Procurement Foundation (SEOPF) Prospective Study. There were no significant differences between the groups with and without polycystic disease in terms of recipient blood group, history of splenectomy, or preformed antibody status. As a group, transplanted polycystic patients underwent native nephrectomy more often, had a better HLA match, received less antilymphocyte serum (ALS), and were slightly older than nonpolycystic patients. Although proportionately fewer polycystic patients received pretransplant transfusions than nonpolycystic patients (P = .002), transfusion was associated with a significant increase in graft survival in the polycystic group (P less than .05), as well as in the nonpolycystic group (P less than .0001). Gene frequency analysis showed no HLA-A, or -B antigen linkage with polycystic disease. No significant differences existed between the polycystic and nonpolycystic groups in terms of overall graft and patient survival. However, transplanted polycystic patients died more frequently from bacterial sepsis (P less than .05), especially from gram-positive organisms (P = .01). Pretransplant bilateral nephrectomy did not affect the incidence of sepsis. However, following graft failure, patients with bilateral native nephrectomy had a greater incidence of severe anemia (50% versus 39%) and death (58% versus 25%; P less than .05) than those with unilateral nephrectomy or no nephrectomy. Treatment with ALS did not significantly improve graft survival in those with polycystic disease. A strong positive correlation was found between patient death and treatment with ALS only in the polycystic group (P less than .01). These findings indicate that the use of pretransplant bilateral native nephrectomy and posttransplant ALS should be judicious in the polycystic patient because they may be associated with increased morbidity and mortality.


Human and animal botulism surveillance in France from 2008 to 2019.
Botulism is a human and animal neurological disease caused by the action of bacterial neurotoxins (botulinum toxins) produced by bacteria from the genus Clostridium. This disease induces flaccid paralysis that can result in respiratory paralysis and heart failure. Due to its serious potential impact on public health, botulism is a closely monitored notifiable disease in France through a case-based passive surveillance system. In humans, this disease is rare, with an average of 10 outbreaks reported each year, mainly due to the consumption of contaminated foods. Type B and to a lesser extend type A are responsible for the majority of cases of foodborne botulism. Each year, an average of 30 outbreaks are recorded on poultry farms, about 20 cases in wild birds and about 10 outbreaks in cattle, involving a large number of animals. Mosaic forms C/D and D/C in birds and cattle, respectively, are the predominant types in animals in France. Types C and D have also been observed to a lesser extent in animals. With the exception of botulinum toxin E, which was exceptionally detected throughout the period in wild birds, the types of botulism found in animal outbreaks are different from those identified in human outbreaks over the last ten years in France and no human botulism outbreaks investigated have been linked to animal botulism. In line with the One Health concept, we present the first integrative approach to the routine surveillance of botulism in humans and animals in France.


9-Bromo-9-borafluorene.
The title compound, C(12)H(8)BBr, crystallizes with three essentially planar mol-ecules (r.m.s. deviations = 0.018, 0.020 and 0.021Å) in the asymmetric unit: since the title compound is rigid, there are no conformational differences between these three mol-ecules. The crystal packing resembles a herringbone pattern.


Recommendations for the appropriate use of anti-inflammatory drugs in the era of the coxibs: defining the role of gastroprotective agents.
Treatment with anti-inflammatory drugs and the analgesic efficacy of conventional nonsteroidal anti-inflammatory drugs (NSAIDs) are compromised by a two- to fourfold increased risk of gastrointestinal complications. This increased risk has resulted in an increasing use of the new selective cyclooxygenase-2 inhibitors or coxibs, which, in clinical trials and outcomes studies, reduced gastrointestinal adverse events by 50% to 65% compared with conventional NSAIDs. However, the coxibs are not available to all patients who need them, and NSAIDs are still widely used. Moreover, treatment with a coxib cannot heal pre-existing gastrointestinal lesions, and cotherapy with an anti-secretory drug or mucosal protective agent may be required. This paper addresses the management of patients with risk factors for gastrointestinal complications who are taking NSAIDs and makes recommendations for the appropriate use of 'gastroprotective' agents (GPAs) in patients who need to take an NSAID or a coxib. When economically possible, a coxib alone is preferable to a conventional NSAID plus a GPA to minimize exposure to potential gastrointestinal damage and avoid unnecessary dual therapy. Patients at high risk require a GPA in addition to a coxib.


Mechanobiology of MicroRNAs in Intervertebral Disk Degeneration.
Intervertebral disk degeneration (IDD) is an intricate pathological process contributing to one of the major causes of low back pain. The degradation of the extracellular matrix (ECM), inflammation, and apoptosis have all been investigated as critical factors involved in the pathology of degenerative disk disease. Additionally, the presence of aberrant microRNAs (miRNAs), conserved molecules that regulate the amount protein post-transcriptionally, may play a crucial role in the pathogenesis of IDD. Research regarding the dysfunction of miRNAs in IDD has been well researched over the past five years. Here, we provide a critical overview of the current knowledge of miRNAs, emphasizing the processes involved in the degenerative disk pathology.


Crystals of DhaA mutants from Rhodococcus rhodochrous NCIMB 13064 diffracted to ultrahigh resolution: crystallization and preliminary diffraction analysis.
The enzyme DhaA from Rhodococcus rhodochrous NCIMB 13064 belongs to the haloalkane dehalogenases, which catalyze the hydrolysis of haloalkanes to the corresponding alcohols. The haloalkane dehalogenase DhaA and its variants can be used to detoxify the industrial pollutant 1,2,3-trichloropropane (TCP). Three mutants named DhaA04, DhaA14 and DhaA15 were constructed in order to study the importance of tunnels connecting the buried active site with the surrounding solvent to the enzymatic activity. All protein mutants were crystallized using the sitting-drop vapour-diffusion method. The crystals of DhaA04 belonged to the orthorhombic space group P2(1)2(1)2(1), while the crystals of the other two mutants DhaA14 and DhaA15 belonged to the triclinic space group P1. Native data sets were collected for the DhaA04, DhaA14 and DhaA15 mutants at beamline X11 of EMBL, DESY, Hamburg to the high resolutions of 1.30, 0.95 and 1.15 A, respectively.


Epidemiology of leprosy on five isolated islands in the Flores Sea, Indonesia.
We conducted a population-based survey on five small islands in South Sulawesi Province (Indonesia) to collect baseline data previous to a chemoprophylactic intervention study aiming at interrupting the transmission of Mycobacterium leprae. Here we describe the present leprosy epidemiology on these geographically isolated islands. Of the 4774 inhabitants living in the study area 4140 were screened for leprosy (coverage: 87%). We identified 96 leprosy patients (85 new and 11 old patients), representing a new case detection rate (CDR) of 205/10 000 and a prevalence rate of 195/10 000. CDRs were similar for males and females. Male patients were more often classified as multibacillary (MB) than women. Of the new patients, 33 (39%) were classified as MB, 16 (19%) as paucibacillary (PB) 2-5 lesions and 36 (42%) as PB single lesion. In this area of high leprosy endemicity leprosy patients were extensively clustered, i.e. not equally distributed among the islands and within the islands among the houses.


Responsiveness of locus ceruleus neurons in hypertensive rats to vasopressin.
We studied the actions of vasopressin administered microiontophoretically onto neurons of the locus ceruleus in rats with deoxycorticosterone-acetate (DOCA)-salt hypertension and in control (normotensive) rats. Rats were studied at 3 days (prehypertensive stage) and 4 to 6 weeks after DOCA-salt treatment (chronic hypertensive stage). Experiments were performed in anesthetized rats using conventional microiontophoretic and single-cell recording techniques. Three days after DOCA-salt administration, the treated rats showed no rise in arterial pressure in comparison with control rats, but 4 to 6 weeks later, the treated rats had significantly greater pressures (p less than 0.01) than controls. Vasopressin administered with currents of 10 to 90 nA for 1 minute produced a current-dependent increase in the firing rate of noradrenergic neurons in all rats. Increases in the firing rate of noradrenergic neurons in DOCA-salt-treated rats, whether in the prehypertensive or the chronic stage, were significantly greater than increases in control rats. These findings indicate that 1) vasopressin can affect neuronal activity in the locus ceruleus and 2) noradrenergic neurons in the locus ceruleus of DOCA-salt-treated rats have an increased responsiveness to the excitatory effects of vasopressin in both prehypertensive and chronic stages of hypertension.


The impact of COVID-19 and strategies for mitigation and suppression in low- and middle-income countries.
The ongoing coronavirus disease 2019 (COVID-19) pandemic poses a severe threat to public health worldwide. We combine data on demography, contact patterns, disease severity, and health care capacity and quality to understand its impact and inform strategies for its control. Younger populations in lower-income countries may reduce overall risk, but limited health system capacity coupled with closer intergenerational contact largely negates this benefit. Mitigation strategies that slow but do not interrupt transmission will still lead to COVID-19 epidemics rapidly overwhelming health systems, with substantial excess deaths in lower-income countries resulting from the poorer health care available. Of countries that have undertaken suppression to date, lower-income countries have acted earlier. However, this will need to be maintained or triggered more frequently in these settings to keep below available health capacity, with associated detrimental consequences for the wider health, well-being, and economies of these countries.


Global and regional left ventricular myocardial deformation measures by magnetic resonance feature tracking in healthy volunteers: comparison with tagging and relevance of gender.
Feature tracking software offers measurements of myocardial strain, velocities and displacement from cine cardiovascular magnetic resonance (CMR) images. We used it to record deformation parameters in healthy adults and compared values to those obtained by tagging. We used TomTec 2D Cardiac Performance Analysis software to derive global, regional and segmental myocardial deformation parameters in 145 healthy volunteers who had steady state free precession (SSFP) cine left ventricular short (basal, mid and apical levels) and long axis views (horizontal long axis, vertical long axis and left ventricular out flow tract) obtained on a 1.5 T Siemens Sonata scanner. 20 subjects also had tagged acquisitions and we compared global and regional deformation values obtained from these with those from Feature Tracking. For globally averaged measurements of strain, only those measured circumferentially in short axis slices showed reasonably good levels of agreement between FT and tagging (limits of agreement -0.06 to 0.04). Longitudinal strain showed wide limits of agreement (-0.16 to 0.03) with evidence of overestimation of strain by FT relative to tagging as the mean of both measures increased. Radial strain was systematically overestimated by FT relative to tagging with very wide limits of agreement extending to as much as 100% of the mean value (-0.01 to 0.23). Reproducibility showed similar relative trends with acceptable global inter-observer variability for circumferential measures (coefficient of variation 4.9%) but poor reproducibility in the radial direction (coefficient of variation 32.3%). Ranges for deformation parameters varied between basal, mid and apical LV levels with higher levels at base compared to apex, and between genders by both FT and tagging. FT measurements of circumferential but not longitudinally or radially directed global strain showed reasonable agreement with tagging and acceptable inter-observer reproducibility. We record provisional ranges of FT deformation parameters at global, regional and segmental levels. They show evidence of variation with gender and myocardial region in the volunteers studied, but have yet to be compared with tagging measurements at the segmental level.


Results of Arthroscopic Ankle Arthrodesis with Fixation Using Two Parallel Headless Compression Screws in a Heterogenic Group of Patients.
As orthopedic surgeons become skilled in ankle arthroscopy technique and evidence -based data is supporting its use, arthroscopic ankle arthrodesis (AAA) will likely continue to increase, but stabilization methods have not been described clearly. We present a technique for two parallel 7.3-mm headless compression screws fixation (HCSs) for AAA in cases of ankle arthritis with different etiology, both traumatic and non-traumatic, including neuromuscular and inflammatory patients. We retrospectively verified 24 consecutive patients (25 ankles) who underwent AAA between 2011 and 2015. The average follow-up was 26 months (range 18 to 52 months). Arthrodesis was performed in 16 patients due to posttraumatic arthritis (in 5 as a sequela of pilon, 6 ankles, 3 tibia fractures, and 2 had arthritis due to chronic instability after lateral ligament injury), in 4 patients due to neuromuscular ankle joint deformities, and in 4 patients due to rheumatoid arthritis. Fusion occurred in 23 joints (92%) over an average of 12 weeks (range 6 to 18 weeks). Ankle arthrodesis was not achieved in 2 joints (8%), both in post-pilon fracture patients. The correct foot alignment was not achieved in 4 feet (16%). None of the treated patients required hardware removal. The presented technique was effective in achieving a high fusion rate in a variety of diseases, decreasing intra- and post-operative hardware complications while maintaining adequate bone stability.


Blockade of microglial activation is neuroprotective in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson disease.
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) damages the nigrostriatal dopaminergic pathway as seen in Parkinson's disease (PD), a common neurodegenerative disorder with no effective protective treatment. Consistent with a role of glial cells in PD neurodegeneration, here we show that minocycline, an approved tetracycline derivative that inhibits microglial activation independently of its antimicrobial properties, mitigates both the demise of nigrostriatal dopaminergic neurons and the formation of nitrotyrosine produced by MPTP. In addition, we show that minocycline not only prevents MPTP-induced activation of microglia but also the formation of mature interleukin-1beta and the activation of NADPH-oxidase and inducible nitric oxide synthase (iNOS), three key microglial-derived cytotoxic mediators. Previously, we demonstrated that ablation of iNOS attenuates MPTP-induced neurotoxicity. Now, we demonstrate that iNOS is not the only microglial-related culprit implicated in MPTP-induced toxicity because mutant iNOS-deficient mice treated with minocycline are more resistant to this neurotoxin than iNOS-deficient mice not treated with minocycline. This study demonstrates that microglial-related inflammatory events play a significant role in the MPTP neurotoxic process and suggests that minocycline may be a valuable neuroprotective agent for the treatment of PD.


Pseudomesotheliomatous carcinoma of the lung with a distinct morphology, immunohistochemistry, and comparative genomic hybridization profile.
We report 4 cases of pseudomesotheliomatous carcinoma of the lung, which has clinical and microscopic features similar to malignant mesothelioma, but with ultrastructural, immunohistochemical, and molecular characteristics suggestive of a histogenesis from type II pneumocytes. Neoplasm grows as a diffuse or solid pattern of large polygonal cells with sharply defined borders. Hale's colloidal iron is positive in the cytoplasm of small groups of cells and, focally, in some intercellular spaces. Ultrastructure showed short microvilli in the surface. Immunohistochemically, tumor cells were positive for thyroid transcription factor-1, podoplanin, mesothelin, pan-cytokeratin, CK-7, CK-19, Ber-EP4, epithelial membrane antigen, apoprotein surfactant A, epidermal growth factor receptor, Leu-M1, carcinoembryonic antigen, E-cadherin, and CD-44 and negative for mesothelioma markers thrombomodulin and calretinin. In some areas, there were small cysts which contained a concentric fibrilar basophilic material apoprotein surfactant A positive. Chromosomal imbalances with comparative genomic hybridization technique were identified with a median of 15 abnormalities per case (range, 1-26): 51 gains, 6 losses, and 1 high-level amplification. The most frequent aberrations among the cases were gains on chromosomes regions 1q, 3q, 5p, 8q, 16p, and 18q and losses in 17p11-13 and 17q 22-q25. High-level amplifications were detected on 7p13-p21. In all cases, there was a characteristic association between the gains on 16p and those on 18q. The 4 cases resulted in death in less than 14 months, in spite of complete surgery and chemotherapy in 2 cases. Our aim is to complement the current understanding of this pseudomesotheliomatous "pneumocytic" carcinoma and alert pathologists to this rare entity to avoid misdiagnosis.


Implementing the birth dose of hepatitis B vaccine in rural Indonesia.
Reaching mothers and their newborn infants around the time of birth with adequate health services has long been a difficult problem in developing countries. In parallel, similar problems have arisen in attempting to deliver hepatitis B (HepB) vaccine to infants born at home in many countries where mother-to-infant transmission is common. It is logical, and supported by experience in Indonesia, to find a combined solution for both problems. The World Health Organization (WHO) recommends that a timely birth dose of HepB vaccine be given, particularly in areas of high vertical transmission of hepatitis B virus (HBV). This can be achieved relatively easily in situations where almost all births occur in health facilities. But where a significant proportion of births occur at home and without birth attendants able to give injections, this is much more difficult. Barriers to the timely administration of the birth dose of HepB vaccine include weakness in policy development and implementation, difficulties in reliably supplying potent vaccine to community level, limited transport, poor communication, limited cold chain capacity, lack of effective training, and lack of a clear delineation of responsibility between health care professionals. Demonstration projects, such as those in Indonesia, suggest that there are significant opportunities to improve the timely delivery of HepB vaccine birth dose in existing maternal and child health programmes where health workers are trained to provide home delivery care.


Aquatic Walking and Swimming Kinematics of Neonate and Juvenile Epaulette Sharks.
The epaulette shark, Hemiscyllium ocellatum, is a small, reef-dwelling, benthic shark that-using its paired fins-can walk, both in and out of water. Within the reef flats, this species experiences short periods of elevated CO2 and hypoxia as well as fluctuating temperatures as reef flats become isolated with the outgoing tide. Past studies have shown that this species is robust (i.e., respiratory and metabolic performance, behavior) to climate change-relevant elevated CO2 levels as well as hypoxia and anoxia tolerant. However, epaulette shark embryos reared under ocean warming conditions hatch earlier and smaller, with altered patterns and coloration, and with higher metabolic costs than their current-day counterparts. Findings to date suggest that this species has adaptations to tolerate some, but perhaps not all, of the challenging conditions predicted for the 21st century. As such, the epaulette shark is emerging as a model system to understand vertebrate physiology in changing oceans. Yet, few studies have investigated the kinematics of walking and swimming, which may be vital to their biological fitness, considering their habitat and propensity for challenging environmental conditions. Given that neonates retain embryonic nutrition via an internalized yolk sac, resulting in a bulbous abdomen, while juveniles actively forage for worms, crustaceans, and small fishes, we hypothesized that difference in body shape over early ontogeny would affect locomotor performance. To test this, we examined neonate and juvenile locomotor kinematics during the three aquatic gaits they utilize-slow-to-medium walking, fast walking, and swimming-using 13 anatomical landmarks along the fins, girdles, and body midline. We found that differences in body shape did not alter kinematics between neonates and juveniles. Overall velocity, fin rotation, axial bending, and tail beat frequency and amplitude were consistent between early life stages. Data suggest that the locomotor kinematics are maintained between neonate and juvenile epaulette sharks, even as their feeding strategy changes. Studying epaulette shark locomotion allows us to understand this-and perhaps related-species' ability to move within and away from challenging conditions in their habitats. Such locomotor traits may not only be key to survival, in general, as a small, benthic mesopredator (i.e., movements required to maneuver into small reef crevices to avoid aerial and aquatic predators), but also be related to their sustained physiological performance under challenging environmental conditions, including those associated with climate change-a topic worthy of future investigation.


Isovolumic loading prevents atrophy of the heterotopically transplanted rat heart.
Heterotopically (infrarenal) transplanted cardiac isografts are histologically normal, spontaneously beating, hemodynamically unloaded hearts that undergo rapid and predictable atrophy. To study the factors that regulate cardiac growth we examined the effect of left ventricular (LV) isovolumic balloon placement on the weight, in vitro protein synthesis rate, and LV RNA content of the transplanted heart. At day 0 the donor LV weight was 367 +/- 8 mg, which decreased to 226 +/- 14 mg (p less than 0.001) after transplantation. Isovolumic loading with a latex balloon (volume, 111 +/- 10 microliters) significantly increased the LV weight of the transplanted heart to 397 +/- 13 mg when compared with that of the unloaded heart 14 days after surgery and prevented the atrophy when compared with the LV weight at day 0. Sham-loaded transplants had LV weights of 256 +/- 17 mg, which did not differ from the LV weight of unloaded transplanted hearts. Protein synthesis rates (nmol lysine/LV/hr) and total LV RNA and LV 18S RNA content were significantly greater in the balloon-loaded hearts when compared with the unloaded isografts and returned to levels similar to those measured in the in situ hearts. The ability of isovolumic loading of the LV to prevent atrophy via increased protein synthesis and the maintenance of LV RNA in the heterotopically transplanted heart further supports the important role of cardiac work in the regulation of cardiac growth.


Unraveling Entropic Rate Acceleration Induced by Solvent Dynamics in Membrane Enzymes.
Enzyme catalysis evolved in an aqueous environment. The influence of solvent dynamics on catalysis is, however, currently poorly understood and usually neglected. The study of water dynamics in enzymes and the associated thermodynamical consequences is highly complex and has involved computer simulations, nuclear magnetic resonance (NMR) experiments, and calorimetry. Water tunnels that connect the active site with the surrounding solvent are key to solvent displacement and dynamics. The protocol herein allows for the engineering of these motifs for water transport, which affects specificity, activity and thermodynamics. By providing a biophysical framework founded on theory and experiments, the method presented herein can be used by researchers without previous expertise in computer modeling or biophysical chemistry. The method will advance our understanding of enzyme catalysis on the molecular level by measuring the enthalpic and entropic changes associated with catalysis by enzyme variants with obstructed water tunnels. The protocol can be used for the study of membrane-bound enzymes and other complex systems. This will enhance our understanding of the importance of solvent reorganization in catalysis as well as provide new catalytic strategies in protein design and engineering.


GOST: A generic ordinal sequential trial design for a treatment trial in an emerging pandemic.
Conducting clinical trials to assess experimental treatments for potentially pandemic infectious diseases is challenging. Since many outbreaks of infectious diseases last only six to eight weeks, there is a need for trial designs that can be implemented rapidly in the face of uncertainty. Outbreaks are sudden and unpredictable and so it is essential that as much planning as possible takes place in advance. Statistical aspects of such trial designs should be evaluated and discussed in readiness for implementation. This paper proposes a generic ordinal sequential trial design (GOST) for a randomised clinical trial comparing an experimental treatment for an emerging infectious disease with standard care. The design is intended as an off-the-shelf, ready-to-use robust and flexible option. The primary endpoint is a categorisation of patient outcome according to an ordinal scale. A sequential approach is adopted, stopping as soon as it is clear that the experimental treatment has an advantage or that sufficient advantage is unlikely to be detected. The properties of the design are evaluated using large-sample theory and verified for moderate sized samples using simulation. The trial is powered to detect a generic clinically relevant difference: namely an odds ratio of 2 for better rather than worse outcomes. Total sample sizes (across both treatments) of between 150 and 300 patients prove to be adequate in many cases, but the precise value depends on both the magnitude of the treatment advantage and the nature of the ordinal scale. An advantage of the approach is that any erroneous assumptions made at the design stage about the proportion of patients falling into each outcome category have little effect on the error probabilities of the study, although they can lead to inaccurate forecasts of sample size. It is important and feasible to pre-determine many of the statistical aspects of an efficient trial design in advance of a disease outbreak. The design can then be tailored to the specific disease under study once its nature is better understood.


Chromatin Is Frequently Unknotted at the Megabase Scale.
Knots in the human genome would greatly impact diverse cellular processes ranging from transcription to gene regulation. To date, it has not been possible to directly examine the genome in vivo for the presence of knots. Recently, methods for serial fluorescent in situ hybridization have made it possible to measure the three-dimensional position of dozens of consecutive genomic loci in vivo. However, the determination of whether genomic trajectories are knotted remains challenging because small errors in the localization of a single locus can transform an unknotted trajectory into a highly knotted trajectory and vice versa. Here, we use stochastic closure analysis to determine if a genomic trajectory is knotted in the setting of experimental noise. We analyze 4727 deposited genomic trajectories of a 2-Mb-long chromatin interval from human chromosome 21. For 243 of these trajectories, their knottedness could be reliably determined despite the possibility of localization errors. Strikingly, in each of these 243 cases, the trajectory was unknotted. We note a potential source of bias insofar as knotted contours may be more difficult to reliably resolve. Nevertheless, our data are consistent with a model in which, at the scales probed, the human genome is often free of knots.


Heightened Responses of the Parahippocampal and Retrosplenial Cortices during Contextualized Recognition of Congruent Objects.
Context sometimes helps make objects more recognizable. Previous studies using functional magnetic resonance imaging (fMRI) have examined regional neural activity when objects have strong or weak associations with their contexts. Such studies have demonstrated that activity in the parahippocampal cortex (PHC) generally corresponds with strong associations between objects and their spatial contexts while retrosplenial cortex (RSC) activity is linked with episodic memory. However these studies investigated objects viewed in associated contexts, but the direct influence of scene on the perception of visual objects has not been widely investigated. We hypothesized that the PHC and RSC may only be engaged for congruent contexts in which the object could typically be found but not for neutral contexts. While in an fMRI scanner, 15 participants rated the recognizability of 152 photographic images of objects, presented within congruent and incongruent contexts. Regions of interest were created to examine PHC and RSC activity using a hypothesis-driven approach. Exploratory analyses were also performed to identify other regional activity. In line with previous studies, PHC and RSC activity emerged when objects were viewed in congruent contexts. Activity in the RSC, inferior parietal lobe (IPL) and fusiform gyrus also emerged. These findings indicate that different brain regions are employed when objects are meaningfully contextualized.


Size-dependent functional response of Xenopus laevis feeding on mosquito larvae.
Predators can play an important role in regulating prey abundance and diversity, determining food web structure and function, and contributing to important ecosystem services, including the regulation of agricultural pests and disease vectors. Thus, the ability to predict predator impact on prey is an important goal in ecology. Often, predators of the same species are assumed to be functionally equivalent, despite considerable individual variation in predator traits known to be important for shaping predator-prey interactions, like body size. This assumption may greatly oversimplify our understanding of within-species functional diversity and undermine our ability to predict predator effects on prey. Here, we examine the degree to which predator-prey interactions are functionally homogenous across a natural range of predator body sizes. Specifically, we quantify the size-dependence of the functional response of African clawed frogs (Xenopus laevis) preying on mosquito larvae (Culex pipiens). Three size classes of predators, small (15-30 mm snout-vent length), medium (50-60 mm) and large (105-120 mm), were presented with five densities of prey to determine functional response type and to estimate search efficiency and handling time parameters generated from the models. The results of mesocosm experiments showed that type of functional response of X. laevis changed with size: small predators exhibited a Type II response, while medium and large predators exhibited Type III responses. Functional response data showed an inversely proportional relationship between predator attack rate and predator size. Small and medium predators had highest and lowest handling time, respectively. The change in functional response with the size of predator suggests that predators with overlapping cohorts may have a dynamic impact on prey populations. Therefore, predicting the functional response of a single size-matched predator in an experiment may misrepresent the predator's potential impact on a prey population.


Prospective Study of Dietary Zinc Intake and Risk of Cardiovascular Disease in Women.
Several animal and human studies have shown that zinc is associated with cellular damage and cardiac dysfunction. This study aims to investigate dietary zinc and the zinc-iron ratio, as predictors of incident cardiovascular disease (CVD) in a large longitudinal study of mid-age Australian women (aged 50-61 years). Data was self-reported and validated food frequency questionnaires were used to assess dietary intake. Energy-adjusted zinc was ranked using quintiles and predictors of incident CVD were examined using stepwise logistic regression. After six years of follow-up, 320 incident CVD cases were established. A positive association between dietary zinc intake, zinc-iron ratio and risk of CVD was observed even after adjusting for potential dietary and non-dietary confounders. Compared to those with the lowest quintile of zinc, those in the highest quintile (Odds Ratio (OR) = 1.67, 95% Confidence Interval (CI) = 1.08-2.62) and zinc-iron ratio (OR = 1.72, 95% CI = 1.05-2.81) had almost twice the odds of developing CVD (p trend = 0.007). This study shows that high dietary zinc intake and zinc-iron ratio is associated with a greater incidence of CVD in women. Further studies are required detailing the source of zinc and iron in diet and their precise roles when compared to other essential nutrients.


A Double-Blind Randomized Comparison of Continuous Interscalene, Supraclavicular, and Suprascapular Blocks for Total Shoulder Arthroplasty.
Continuous brachial plexus blocks at the interscalene level are associated with known diaphragm dysfunction from phrenic nerve paresis. More distal blocks along the brachial plexus may provide postsurgical analgesia while potentially having less effect on diaphragm function. Continuous interscalene, continuous supraclavicular, and continuous suprascapular nerve blocks were evaluated for respiratory function and analgesia after total shoulder arthroplasty. After ethics board approval, subjects presenting for total shoulder arthroplasty were planned for randomization in a 1:1:1 ratio of a continuous interscalene, supraclavicular, or suprascapular block. The primary outcome was the assessment of vital capacity after 24 hours of continuous nerve block infusion (6 mL/h; 0.2% ropivacaine), without an initial bolus of local anesthetic during catheter placement. Additional outcomes included diaphragm excursion, pain scores, opioid consumption, and adverse effects. Seventy-five subjects, 25 per group, completed the study. At 24 hours of continuous infusion only (no initial block bolus), the mean vital capacity reduction in the continuous interscalene control group was 991 mL (95% confidence interval [CI], 820-1162). Compared to the interscalene group, the continuous supraclavicular group had a mean vital capacity reduction of 803 mL (95% CI, 616-991; P = 0.322). The continuous suprascapular group had a significantly improved mean vital capacity reduction of 464 mL (95% CI, 289-639; P < 0.001) when similarly compared against the interscalene group. A relative compromise in ultrasound-measured diaphragm excursion was identified in the interscalene group compared to both the supraclavicular group (P = 0.012) and the suprascapular group (P < 0.001). Mean pain scores on an 11-point scale (2.2, 1.6, and 2.6) and 24-hour opioid consumption (13.8 mg, 9.9 mg, and 21.8 mg) for groups interscalene, supraclavicular, and suprascapular, respectively, did not show statistically significant differences. Less adverse effects (Horner syndrome, dyspnea, and hoarseness) were noted in the suprascapular group when compared with the interscalene group (P = 0.002). A continuous suprascapular block may be a useful analgesic alternative to the interscalene or supraclavicular approaches when the preservation of lung function is a priority after shoulder replacement surgery.


Global multidimensional poverty and COVID-19: A decade of progress at risk?
According to the global Multidimensional Poverty Index (MPI), an internationally comparable measure, poverty in developing countries has fallen substantially over the last 15 years. The COVID-19 pandemic and associated economic contraction are negatively impacting multiple dimensions of poverty and jeopardising this progress. This paper uses recent assessments of food insecurity and school closures made by UN agencies to inform microsimulations of potential short-term impacts of the pandemic under alternative scenarios. These simulations use the nationally representative datasets underlying the 2020 update of the global MPI. Because these datasets were collected in various years before the pandemic, we develop models to translate the simulated impacts to 2020. Our approach accounts for the country-specific joint distribution of deprivations in the simulations, recent poverty reduction trends, and resulting differences in the responsiveness of the global MPI to the scenarios. Aggregating results across 70 countries that account for 89% of the global poor according to the 2020 global MPI, we find that the potential setback to multidimensional poverty reduction is between 3.6 and 9.9 years under the alternative scenarios. We argue that the extent to which such disruptions result in persistent increases of poverty and deprivations may be attenuated by appropriate policy responses.


Detection of specific IgE antibodies in parasite diseases.
Activation of Th1 or Th2 cells is associated with production of specific immunoglobulin isotypes, offering the opportunity to use antibody measurement for evaluation of T cell function. Schistosomiasis and visceral leishmaniasis are diseases associated with Th2 activation. However, an IgE response is not always detected in these patients. In the present study we evaluated specific IgE antibodies to S. mansoni and L. chagasi antigens by ELISA after depletion of serum IgG with protein G immobilized on Sepharose beads or RF-absorbent (purified sheep IgG antibodies anti-human IgG). In schistosomiasis patients, specific IgE to SWAP antigen was demonstrable in only 10 of 21 patients (48%) (mean absorbance +/- SD = 0.102 +/- 0.195) when unabsorbed serum was used. Depletion of IgG with protein G increased the number of specific IgE-positive tests to 13 (62%) and the use of RF-absorbent increased the number of positive results to 20 (95%) (mean absorbances +/- SD = 0.303 +/- 0. 455 and 0.374 +/- 0.477, respectively). Specific IgE anti-L. chagasi antibodies were not detected in unabsorbed serum from visceral leishmaniasis patients. When IgG was depleted with protein G, IgE antibodies were detected in only 3 (11%) of 27 patients, and the use of RF-absorbent permitted the detection of this isotype in all 27 visceral leishmaniasis sera tested (mean absorbance +/- SD = 0.104 +/- 0.03). These data show that the presence of IgG antibodies may prevent the detection of a specific IgE response in these parasite diseases. RF-absorbent, a reagent that blocks IgG-binding sites and also removes rheumatoid factor, was more efficient than protein G for the demonstration of specific IgE antibodies.


Cholera toxin B subunit binding does not correlate with GM1 expression: a study using mouse embryonic neural precursor cells.
Gangliosides, sialic acid-containing glycosphingolipids, are ubiquitously expressed in all eukaryotic cells and are primarily localized in the plasma membrane. Cholera toxin B subunit (Ctxb), a component of a heat-labile enterotoxin produced by Vibrio cholerae, has been frequently used as a probe to detect GM1 ganglioside because of its high affinity for this glycolipid. In this study, we evaluated the reactivity of Ctxb and the expression of GM1 in mouse embryonic neuroepithelial cells (NECs). Analysis of Ctxb reactivity of NECs based on flow cytometry revealed that about 80% of the cells are Ctxb positive. A detailed biochemical analysis, however, indicated that GM1 was expressed in NECs in barely detectable quantities. Thus, it was thought that reactivity of Ctxb in the NECs could arise from high-affinity interaction with GM1. Because Ctxb is commonly used as a reagent for flow cytometry and GM1 cell staining, we recommend that using this reagent alone would be inconclusive and that biochemical analysis of GM1 should also be performed to avoid overestimation of GM1 expression and/or mischaracterization of the ganglioside species.


Evaluating polar pesticide pollution with a combined approach: a survey of agricultural practices and POCIS passive samplers in a Tunisian lagoon watershed.
A study of pesticides in the Bizerte lagoon watershed on the Mediterranean coast of Tunisia showed that herbicides and fungicides are the most commonly used compounds. A survey was made of selected farmers. Pesticide contamination was monitored in the water column and sediments at four selected sampling sites (lagoon (A) and in three oueds-Chegui (B), Garaa (C), and Tinja (D)). Polar organic chemical integrative samplers (POCIS) were used to assess pesticide contamination. Thirty-two pesticides were investigated; the total concentration of active ingredients ranged from 35.9 ng L-1 in Tinja oued to 1246 ng L-1 in Chegui oued. In the lagoon, the total concentration of pesticides was 67.7 ng L-1. In the sediments, the highest concentration was measured in Chegui oued in the spring (31 ng g-1 dw). The main compounds found in the analyzed sediments were prosulfocarb and tebuconazole molecules.


Autocrine regulation of macrophage activation via exocytosis of ATP and activation of P2Y11 receptor.
It is important to understand the mechanisms that regulate macrophage activation to establish novel therapies for inflammatory diseases, such as sepsis; a systemic inflammatory response syndrome generally caused by bacterial lipopolysaccharide (LPS). In this study, we investigated the involvement of extracellular ATP-mediated autocrine signaling in LPS-induced macrophage activation. We show here that ATP release via exocytosis, followed by activation of P2Y11 receptor, is a major pathway of the macrophage activation, leading to release of cytokines. Treatment of human monocyte THP-1 cells with LPS induced rapid ATP release from cells, and this release was blocked by knockdown of SLC17A9 (vesicular nucleotide transporter, VNUT), which is responsible for exocytosis of ATP. ATP-enriched vesicles were found in cytosol of THP-1 cells. These data suggest the involvement of vesicular exocytosis in the release of ATP. Knockdown of SLC17A9, the P2Y11 antagonist NF157 or knockdown of P2Y11 receptor significantly suppressed both M1-type polarization and IL-6 production in THP-1 cells, indicating an important role of activation of P2Y11 receptor by released ATP in macrophage activation. Next, the effect of NF157 on LPS-induced immune activation was examined in vivo. Administration of LPS to mice caused increase of serum IL-1ß, IL-6, IL-12 and TNF-alpha levels at 3-24 h after the administration. Pre-treatment of LPS-treated mice with NF157 suppressed both elevation of proinflammatory cytokines in serum and M1 polarization of peritoneal/spleen macrophages. Moreover, post-treatment with NF157 at 30 min after administration of LPS also suppressed the elevation of serum cytokines levels. We conclude that vesicular exocytosis of ATP and autocrine, positive feedback through P2Y11 receptors is required for the effective activation of macrophages. Consequently, P2Y11 receptor antagonists may be drug candidates for treatment of inflammatory diseases such as sepsis.


Olfactory and gustatory function in irritable bowel syndrome.
Irritable bowel syndrome (IBS) is the most common, functional disorder diagnosed by gastroenterologists. It is still unclear whether IBS has a central etiology, e.g., hyperreactivity of the brain, or a peripheral etiology, e.g., stimulation of olfactory/gustatory receptors on enterochromaffin cells, followed by serotonin release and changed gut motility. Testing the odor identification (ID), odor discrimination (DIS) and odor threshold (THR) as well as the total taste and the taste qualities "sweet", "sour", "salty" and "bitter" should be of help for determining the etiology. To our knowledge, this is the first study investigating the olfactory/gustatory function in IBS patients. The olfactory/gustatory function of 43 patients (32 women, 11 men) suffering from IBS as defined by the ROME III criteria was investigated by means of validated tests (Sniffin' Sticks and taste strips). Compared to normative data, scores of THR were decreased and scores of ID and DIS were increased in IBS patients. Additionally, when compared to normative data, there was no difference in the taste function of IBS patients. Assuming that THR reflects more the peripheral olfactory function, whereas ID and DIS are influenced by central activity, and that taste did not differ in IBS patients compared to normative data, this supports the idea of a central etiology of IBS.


Developmental processes in face perception.
Understanding the developmental origins of face recognition has been the goal of many studies of various approaches. Contributions of experience-expectant mechanisms (early component), like perceptual narrowing, and lifetime experience (late component) to face processing remain elusive. By investigating captive chimpanzees of varying age, a rare case of a species with lifelong exposure to non-conspecific faces at distinctive levels of experience, we can disentangle developmental components in face recognition. We found an advantage in discriminating chimpanzee above human faces in young chimpanzees, reflecting a predominant contribution of an early component that drives the perceptual system towards the conspecific morphology, and an advantage for human above chimpanzee faces in old chimpanzees, reflecting a predominant late component that shapes the perceptual system along the critical dimensions of the face exposed to. We simulate the contribution of early and late components using computational modeling and mathematically describe the underlying functions.


Characterisation and mechanisms of bradykinin-evoked pain in man using iontophoresis.
Bradykinin (BK) is an inflammatory mediator that can evoke oedema and vasodilatation, and is a potent algogen signalling via the B1 and B2 G-protein coupled receptors. In naïve skin, BK is effective via constitutively expressed B2 receptors (B2R), while B1 receptors (B1R) are purported to be upregulated by inflammation. The aim of this investigation was to optimise BK delivery to investigate the algesic effects of BK and how these are modulated by inflammation. BK iontophoresis evoked dose- and temperature-dependent pain and neurogenic erythema, as well as thermal and mechanical hyperalgesia (P < 0.001 vs saline control). To differentiate the direct effects of BK from indirect effects mediated by histamine released from mast cells (MCs), skin was pretreated with compound 4880 to degranulate the MCs prior to BK challenge. The early phase of BK-evoked pain was reduced in degranulated skin (P < 0.001), while thermal and mechanical sensitisation, wheal, and flare were still evident. In contrast to BK, the B1R selective agonist des-Arg9-BK failed to induce pain or sensitise naïve skin. However, following skin inflammation induced by ultraviolet B irradiation, this compound produced a robust pain response. We have optimised a versatile experimental model by which BK and its analogues can be administered to human skin. We have found that there is an early phase of BK-induced pain which partly depends on the release of inflammatory mediators by MCs; however, subsequent hyperalgesia is not dependent on MC degranulation. In naïve skin, B2R signaling predominates, however, cutaneous inflammation results in enhanced B1R responses.


Self-organization of periodic patterns by dissociated feather mesenchymal cells and the regulation of size, number and spacing of primordia.
Periodic patterning is a fundamental organizing process in biology. Using a feather reconstitution assay, we traced back to the initial stage of the patterning process. Cells started from an equivalent state and self-organized into a periodic pattern without previous cues or sequential propagation. When different numbers of dissociated mesenchymal cells were confronted with a piece of same-sized epithelium, the size of feather primordia remained constant, not the number or interbud spacing, suggesting size determination is intrinsic to dissociated cells. Increasing bone morphogenetic protein (BMP) receptor expression in mesenchymal cells decreased the size of primordia while antagonizing the BMP pathway with Noggin increased the size of primordia. A threshold number of mesenchymal cells with a basal level of adhesion molecules such as NCAM were sufficient to trigger the patterning process. The process is best visualized by the progressive restriction of beta-catenin transcripts in the epidermis. Therefore, feather size, number and spacing are modulated through the available morphogen ligands and receptors in the system.


Vaccine-induced antibodies to herpes simplex virus glycoprotein D epitopes involved in virus entry and cell-to-cell spread correlate with protection against genital disease in guinea pigs.
Herpes simplex virus type 2 (HSV-2) glycoprotein D (gD2) subunit antigen is included in many preclinical candidate vaccines. The rationale for including gD2 is to produce antibodies that block crucial gD2 epitopes involved in virus entry and cell-to-cell spread. HSV-2 gD2 was the only antigen in the Herpevac Trial for Women that protected against HSV-1 genital infection but not HSV-2. In that trial, a correlation was detected between gD2 ELISA titers and protection against HSV-1, supporting the importance of antibodies. A possible explanation for the lack of protection against HSV-2 was that HSV-2 neutralization titers were low, four-fold lower than to HSV-1. Here, we evaluated neutralization titers and epitope-specific antibody responses to crucial gD2 epitopes involved in virus entry and cell-to-cell spread as correlates of immune protection against genital lesions in immunized guinea pigs. We detected a strong correlation between neutralizing antibodies and protection against genital disease. We used a high throughput biosensor competition assay to measure epitope-specific responses to seven crucial gD2 linear and conformational epitopes involved in virus entry and spread. Some animals produced antibodies to most crucial epitopes while others produced antibodies to few. The number of epitopes recognized by guinea pig immune serum correlated with protection against genital lesions. We confirmed the importance of antibodies to each crucial epitope using monoclonal antibody passive transfer that improved survival and reduced genital disease in mice after HSV-2 genital challenge. We re-evaluated our prior study of epitope-specific antibody responses in women in the Herpevac Trial. Humans produced antibodies that blocked significantly fewer crucial gD2 epitopes than guinea pigs, and antibody responses in humans to some linear epitopes were virtually absent. Neutralizing antibody titers and epitope-specific antibody responses are important immune parameters to evaluate in future Phase I/II prophylactic human vaccine trials that contain gD2 antigen.


Curation of cancer hallmark-based genes and pathways for in silico characterization of chemical carcinogenesis.
Exposure to toxic substances in the environment is one of the most important causes of cancer. However, the time-consuming process for the identification and characterization of carcinogens is not applicable to a huge amount of testing chemicals. The data gaps make the carcinogenic risk uncontrollable. An efficient and effective way of prioritizing chemicals of carcinogenic concern with interpretable mechanism information is highly desirable. This study presents a curation work for genes and pathways associated with 11 hallmarks of cancer (HOCs) reported by the Halifax Project. To demonstrate the usefulness of the curated HOC data, the interacting HOC genes and affected HOC pathways of chemicals of the three carcinogen lists from IARC, NTP and EPA were analyzed using the in silico toxicogenomics ChemDIS system. Results showed that a higher number of affected HOCs were observed for known carcinogens than the other chemicals. The curated HOC data is expected to be useful for prioritizing chemicals of carcinogenic concern. Database URL: The HOC database is available at https://github.com/hocdb-KMU-TMU/hocdb and the website of Database journal as Supplementary Data.


Protective antiviral antibody responses in a mouse model of influenza virus infection require TACI.
Antiviral Abs, for example those produced in response to influenza virus infection, are critical for virus neutralization and defense against secondary infection. While the half-life of Abs is short, Ab titers can last a lifetime due to a subset of the Ab-secreting cells (ASCs) that is long lived. However, the mechanisms governing ASC longevity are poorly understood. Here, we have identified a critical role for extrinsic cytokine signals in the survival of respiratory tract ASCs in a mouse model of influenza infection. Irradiation of mice at various time points after influenza virus infection markedly diminished numbers of lung ASCs, suggesting that they are short-lived and require extrinsic factors in order to persist. Neutralization of the TNF superfamily cytokines B lymphocyte stimulator (BLyS; also known as BAFF) and a proliferation-inducing ligand (APRIL) reduced numbers of antiviral ASCs in the lungs and bone marrow, whereas ASCs in the spleen and lung-draining lymph node were surprisingly unaffected. Mice deficient in transmembrane activator and calcium-modulator and cyclophilin ligand interactor (TACI), a receptor for BLyS and APRIL, mounted an initial antiviral B cell response similar to that generated in WT mice but failed to sustain protective Ab titers in the airways and serum, leading to increased susceptibility to secondary viral challenge. These studies highlight the importance of TACI signaling for the maintenance of ASCs and protection against influenza virus infection.


Antibodies for HIV treatment and prevention: window of opportunity?
Monoclonal antibodies are routinely used as therapeutics in a number of disease settings and have thus also been explored as potential treatment for human immunodeficiency virus (HIV)-1 infection. Antibodies targeting viral antigens, and those directed to the cellular receptors, have been considered for use in prevention and therapy. For virus-targeted antibodies, attention has focused primarily on their neutralizing activity, but such antibodies also have the potential to exert antiviral effects via effector functions, such as antibody-dependent cellular cytotoxicity (ADCC), opsonization, or complement activation. Anti-cell antibodies act through occlusion or down-modulation of the viral receptors with notable impact in vivo, as recent trials have shown. This review summarizes the diverse specificities and modes of action of therapeutic antibodies against HIV-1 infection. Successes, challenges, and future opportunities of harnessing antibodies for therapy of HIV-1 infection are discussed.


The value of site preparedness studies for future implementation of phase 2/IIb/III HIV prevention trials: experience from the HPTN 055 study.
To evaluate the preparedness for phase 2/IIb/III microbicide trials at 4 clinical trial sites: Durban and Hlabisa (South Africa), Lusaka (Zambia), and Moshi (Tanzania). A prospective cohort study was undertaken to assess site suitability for microbicide efficacy studies. Study objectives included assessing sites' ability to recruit and retain high-risk women with the appropriate HIV incidence rates needed to conduct microbicide efficacy studies. Nine hundred fifty-eight consenting women were enrolled and followed for up to 1 year. Demographic, behavioral, laboratory, and clinical data were collected to determine the incidence rates of HIV, sexually transmitted infections, and pregnancy. Accrual was completed in 6.3, 6.7, 7.1, and 8.3 months in Durban, Hlabisa, Moshi, and Lusaka, respectively. The highest month 12 participant retention rate was recorded in Durban (97%), followed by Hlabisa (94%), Moshi (86%), and Lusaka (93%). Mean overall age of enrolled participants was 28.6 years (ranging from 27.0 to 32.2 years) across sites. Despite condom counseling, rates of condom use were slightly lower at study end. Pregnancy incidence in the study as a whole was 20.2 per 100 women-years (wy). Overall HIV prevalence was 32.5%, and overall HIV incidence was 3.8 per 100 wy (95% confidence interval [CI]: 2.6 to 5.2). HIV incidence per site was 5.3 per 100 wy in Durban (95% CI: 2.7 to 9.2), 6.2 per 100 wy in Hlabisa (95% CI: 3.4 to 10.5); 2.6 per 100 wy in Lusaka (95% CI: 1.0 to 5.8), and 1.4 per 100 wy in Moshi (95% CI: 0.3 to 4.0). Preparatory studies provide accurate local estimates of HIV incidence, recruitment and retention rates, and behavioral characteristics of targeted populations for large-scale clinical trials. Determining these factors allows for better preparation for design, sample size, and appropriate population for future selection of trial sites. Because of the lower than expected HIV incidence observed at the Moshi site, only the South African and Zambian sites were selected for the phase 2/IIb trial.


Resprouting as a key functional trait: how buds, protection and resources drive persistence after fire.
Resprouting as a response to disturbance is now widely recognized as a key functional trait among woody plants and as the basis for the persistence niche. However, the underlying mechanisms that define resprouting responses to disturbance are poorly conceptualized. Resprouting ability is constrained by the interaction of the disturbance regime that depletes the buds and resources needed to fund resprouting, and the environment that drives growth and resource allocation. We develop a buds-protection-resources (BPR) framework for understanding resprouting in fire-prone ecosystems, based on bud bank location, bud protection, and how buds are resourced. Using this framework we go beyond earlier emphases on basal resprouting and highlight the importance of apical, epicormic and below-ground resprouting to the persistence niche. The BPR framework provides insights into: resprouting typologies that include both fire resisters (i.e. survive fire but do not resprout) and fire resprouters; the methods by which buds escape fire effects, such as thick bark; and the predictability of community assembly of resprouting types in relation to site productivity, disturbance regime and competition. Furthermore, predicting the consequences of global change is enhanced by the BPR framework because it potentially forecasts the retention or loss of above-ground biomass.


Bench-to-bedside review: endotoxin tolerance as a model of leukocyte reprogramming in sepsis.
Endotoxin tolerance is defined as a reduced responsiveness to a lipopolysaccharide (LPS) challenge following a first encounter with endotoxin. Endotoxin tolerance protects against a lethal challenge of LPS and prevents infection and ischemia-reperfusion damage. Endotoxin tolerance is paralleled by a dramatic reduction of tumor necrosis factor (TNF) production and some other cytokines in response to LPS. Endotoxin tolerance involves the participation of macrophages and mediators, such as glucocorticoids, prostaglandins, IL-10, and transforming growth factor-beta. Endotoxin tolerance is accompanied by the up-regulation of inhibitory molecules that down-regulate the Toll-like receptor (TLR)4-dependent signaling pathway. Cross-tolerance between LPS and other TLR specific ligands, as well as IL-1 and TNF, has been regularly reported. A similar loss of LPS reactivity has been repeatedly reported in circulating leukocytes of septic patients and in patients with non-infectious systemic inflammation response syndrome (SIRS). Studies on cellular signaling within leukocytes from septic and SIRS patients reveal numerous alterations reminiscent of those observed in endotoxin tolerant cells. However, altered responsiveness to LPS of leukocytes from sepsis and SIRS patients is not synonymous with a global down-regulation of cellular reactivity. The term 'cellular reprogramming', which has been proposed to qualify the process of endotoxin tolerance, defines well the immune status of circulating leukocytes in septic and SIRS patients.


Genome-wide analysis of the auxin/indoleacetic acid (Aux/IAA) gene family in allotetraploid rapeseed (Brassica napus L.).
Auxin/Indoleacetic acid (Aux/IAA) genes participate in the auxin signaling pathway and play key roles in plant growth and development. Although the Aux/IAA gene family has been identified in many plants, within allotetraploid Brassica napus little is known. In this study, a total of 119 Aux/IAA genes were found in the genome of B. napus. They were distributed non-randomly across all 19 chromosomes and other non-anchored random scaffolds, with a symmetric distribution in the A and C subgenomes. Evolutionary and comparative analysis revealed that 111 (94.1%) B. napus Aux/IAA genes were multiplied due to ancestral Brassica genome triplication and recent allotetraploidy from B. rapa and B. oleracea. Phylogenetic analysis indicated seven subgroups containing 29 orthologous gene sets and two Brassica-specific gene sets. Structures of genes and proteins varied across different genes but were conserved among homologous genes in B. napus. Furthermore, analysis of transcriptional profiles revealed that the expression patterns of Aux/IAA genes in B. napus were tissue dependent. Auxin-responsive elements tend to be distributed in the proximal region of promoters, and are significantly associated with early exogenous auxin up-regulation. Members of the Aux/IAA gene family were identified and analyzed comprehensively in the allotetraploid B. napus genome. This analysis provides a deeper understanding of diversification of the Aux/IAA gene family and will facilitate further dissection of Aux/IAA gene function in B. napus.


Effectiveness of the VAMOS Strategy for Increasing Physical Activity and Healthy Dietary Habits: A Randomized Controlled Community Trial.
This study aimed to evaluate the effectiveness of the VAMOS strategy (Health-Improving Active Life) in improving physical activity (PA), dietary habits, and anthropometric variables of primary health care (PHC) users in Brazil. A randomized controlled community trial was conducted at two units of the Health Academy Program (HAP; a service provided by PHC), which were randomly assigned either to control group (CG) or intervention group (IG). Participants in both groups (CG = 156 and IG = 135) took part in physical activity classes provided by HAP facilities with those in IG also participating in the VAMOS strategy for 12 weeks. This strategy is based on social cognitive theory. The main behavioral constructs addressed were self-efficacy, goal setting, self-monitoring, identification of social support and barriers, and solutions for the identified barriers. Physical activity was measured with accelerometers, and nutritional status was assessed using dietary habits questionnaires and anthropometric measurements. Intention-to-treat analysis revealed that participants in IG increased the daily time of moderate-vigorous PA and the frequency of raw vegetable intake, while the intake of ultra-processed foods was reduced. Weight loss among participants who were classified as overweight/obese at baseline was observed in the intervention group compared to control. These results suggest that the VAMOS strategy was effective in increasing PA, healthy dietary habits, and decreasing weight among PHC users. Therefore, VAMOS could be used as a strategy to strengthen individuals' autonomy regarding healthy choices and improve their overall health.


Differential genome evolution between companion symbionts in an insect-bacterial symbiosis.
Obligate symbioses with bacteria allow insects to feed on otherwise unsuitable diets. Some symbionts have extremely reduced genomes and have lost many genes considered to be essential in other bacteria. To understand how symbiont genome degeneration proceeds, we compared the genomes of symbionts in two leafhopper species, Homalodisca vitripennis (glassy-winged sharpshooter [GWSS]) and Graphocephala atropunctata (blue-green sharpshooter [BGSS]) (Hemiptera: Cicadellidae). Each host species is associated with the anciently acquired "Candidatus Sulcia muelleri" (Bacteroidetes) and the more recently acquired "Candidatus Baumannia cicadellinicola" (Gammaproteobacteria). BGSS "Ca. Baumannia" retains 89 genes that are absent from GWSS "Ca. Baumannia"; these underlie central cellular functions, including cell envelope biogenesis, cellular replication, and stress response. In contrast, "Ca. Sulcia" strains differ by only a few genes. Although GWSS "Ca. Baumannia" cells are spherical or pleomorphic (a convergent trait of obligate symbionts), electron microscopy reveals that BGSS "Ca. Baumannia" maintains a rod shape, possibly due to its retention of genes involved in cell envelope biogenesis and integrity. Phylogenomic results suggest that "Ca. Baumannia" is derived from the clade consisting of Sodalis and relatives, a group that has evolved symbiotic associations with numerous insect hosts. Finally, the rates of synonymous and nonsynonymous substitutions are higher in "Ca. Baumannia" than in "Ca. Sulcia," which may be due to a lower mutation rate in the latter. Taken together, our results suggest that the two "Ca. Baumannia" genomes represent different stages of genome reduction in which many essential functions are being lost and likely compensated by hosts. "Ca. Sulcia" exhibits much greater genome stability and slower sequence evolution, although the mechanisms underlying these differences are poorly understood. In obligate animal-bacterial symbioses, bacteria experience extreme patterns of genome evolution, including massive gene loss and rapid evolution. However, little is known about this process, particularly in systems with complementary bacterial partners. To understand whether genome evolution impacts symbiont types equally and whether lineages follow the same evolutionary path, we sequenced the genomes of two coresident symbiotic bacteria from a plant sap-feeding insect and compared them to the symbionts from a related host species. We found that the older symbiont has a highly reduced genome with low rates of mutation and gene loss. In contrast, the younger symbiont has a larger genome that exhibits higher mutation rates and varies dramatically in the retention of genes related to cell wall biogenesis, cellular replication, and stress response. We conclude that while symbiotic bacteria evolve toward tiny genomes, this process is shaped by different selection intensities that may reflect the different ages and metabolic roles of symbiont types.


Transcriptional analysis of micro-dissected articular cartilage in post-traumatic murine osteoarthritis.
Identify gene changes in articular cartilage of the medial tibial plateau (MTP) at 2, 4 and 8 weeks after destabilisation of the medial meniscus (DMM) in mice. Compare our data with previously published datasets to ascertain dysregulated pathways and genes in osteoarthritis (OA). RNA was extracted from the ipsilateral and contralateral MTP cartilage, amplified, labelled and hybridized on Illumina WGv2 microarrays. Results were confirmed by real-time polymerase chain reaction (PCR) for selected genes. Transcriptional analysis and network reconstruction revealed changes in extracellular matrix and cytoskeletal genes induced by DMM. TGFβ signalling pathway and complement and coagulation cascade genes were regulated at 2 weeks. Fibronectin (Fn1) is a hub in a reconstructed network at 2 weeks. Regulated genes decrease over time. By 8 weeks fibromodulin (Fmod) and tenascin N (Tnn) are the only dysregulated genes present in the DMM operated knees. Comparison with human and rodent published gene sets identified genes overlapping between our array and eight other studies. Cartilage contributes a minute percentage to the RNA extracted from the whole joint (<0.2%), yet is sensitive to changes in gene expression post-DMM. The post-DMM transcriptional reprogramming wanes over time dissipating by 8 weeks. Common pathways between published gene sets include focal adhesion, regulation of actin cytoskeleton and TGFβ. Common genes include Jagged 1 (Jag1), Tetraspanin 2 (Tspan2), neuroblastoma, suppression of tumourigenicity 1 (Nbl1) and N-myc downstream regulated gene 2 (Ndrg2). The concomitant genes and pathways we identify may warrant further investigation as biomarkers or modulators of OA.


Early immune markers associated with Mycobacterium avium subsp. paratuberculosis infection in a neonatal calf model.
The objective of this study was to observe early markers of cell-mediated immunity in naïve calves infected with Mycobacterium avium subsp. paratuberculosis and how expression of these markers evolved over the 12-month period of infection. Groups for experimental infection included control (noninfected), oral (infected orally with M. avium subsp. paratuberculosis strain K-10), oral/DXM (pretreatment with dexamethasone before oral inoculation), intraperitoneal (i.p.) inoculation, and oral/M (oral inoculation with mucosal scrapings from a cow with clinical disease) groups. One of the earliest markers to emerge was antigen-specific gamma interferon (IFN-γ). Only i.p. inoculated calves had detectable antigen-specific IFN-γ responses at 7 days, with responses of the other infection groups becoming detectable at 90 and 120 days. All infection groups maintained robust IFN-γ responses for the remainder of the study. At 1 month, calves in the oral and oral/M groups had higher antigen-stimulated interleukin-10 (IL-10) levels than calves in the other treatment groups, but IL-10 secretion declined by 12 months for all calves. T-cell activation markers such as CD25, CD26, CD45RO, and CD5 were significantly upregulated in infected calves compared to noninfected controls. Oral inoculation of calves resulted in significantly increased antigen-specific lymphocyte proliferation at 9 and 12 months, as well as inducible nitric oxide synthase (iNOS) secretion at 6 and 12 months. These results demonstrate that infection of naïve calves with M. avium subsp. paratuberculosis invoked early immunologic responses characterized by robust antigen-specific IFN-γ responses and induction of CD25 and CD45RO expression on T-cell subsets. These were followed by antigen-specific lymphocyte proliferation, iNOS secretion, and expression of CD26 and CD5(bright) markers in the latter part of the 12-month study.


Analysis of proximal and distal muscle activity during handwriting tasks.
In this study we sought to describe upper-extremity proximal and distal muscle activity in typically developing children during a handwriting task and to explore the relationship between muscle activity and speed and quality of writing. We evaluated 35 third- and fourth-grade Israeli children using the Alef-Alef Ktav Yad Hebrew Handwriting Test. Simultaneously, we recorded the participants' upper trapezius and thumb muscle activity by surface electromyography. Using the coefficient of variation (standard deviation divided by mean amplitude) as a measure of variability within each muscle, we analyzed differences in muscle activity variability within and between muscles. The proximal muscle displayed significantly less variability than the distal muscles. Decreased variability in proximal muscle activity was associated with decreased variability in distal muscle activity, and decreased variability in the distal muscles was significantly associated with faster speed of writing. The lower amount of variability exhibited in the proximal muscle compared with the distal muscles seems to indicate that the proximal muscle functions as a stabilizer during a handwriting task. In addition, decreased variability in both proximal and distal muscle activity appears to be more economical and is related to faster writing speed. Knowledge of the type of proximal and distal muscle activity used during handwriting can help occupational therapists plan treatment for children with handwriting disabilities.


Manifestation of malaria in Mangaluru, southern India.
Severe and fatal vivax malaria is increasingly reported from India. In Mangaluru, southern India, malaria is focused in urban areas and associated with importation by migrant workers. In Wenlock Hospital, the largest governmental hospital, the clinical, parasitological and biochemical characteristics of malaria patients were assessed. During the peak malaria season in 2015 (June to December), outpatients were interviewed and clinically assessed. Malaria was ascertained by microscopy and PCR assays, concentrations of haemoglobin, creatinine and bilirubin, as well as thrombocyte count, were determined, and severe malaria was defined according to WHO criteria. Among 909 malaria patients, the vast majority was male (93%), adult (median, 26 years) and of low socio-economic status. Roughly half of them were migrants from beyond the local Karnataka state, mostly from northern and northeastern states. Vivax malaria (69.6%) predominated over mixed Plasmodium vivax-Plasmodium falciparum infection (21.3%) and falciparum malaria (9.0%). The geometric mean parasite density was 3412/µL. As compared to vivax malaria, patients with falciparum malaria had higher parasite density and more frequently showed impaired general condition, affected consciousness and splenomegaly. Also, they tended to more commonly have anaemia and increased creatinine levels, and to be hospitalized (7.3%). Mixed-species infections largely assumed an interim position. Severe malaria (3.5%) was not associated with parasite species. No fatality occurred. In this study, uncomplicated cases of malaria predominated, with P. falciparum causing slightly more intense manifestation. Severe malaria was infrequent and fatalities absent. This contrasts with the reported pattern of manifestation in other parts of India, which requires the analysis of underlying causes.


Renal denervation: tips and tricks to perform a technically successful procedure.
To most practitioners involved in catheter-based interventions, percutaneous renal sympathetic denervation is not technically challenging. However, under specific clinical circumstances (e.g., renal insufficiency) or when faced with more complex abdominal aortic anatomy (e.g., tortuosity) some procedural tips may come in handy. Here we review the equipment, antiplatelet and anticoagulant strategy as well as the procedural technique, including tips and tricks for the successful performance of catheter-based renal denervation. Among other topics, carbon dioxide angiography and brachial artery access are discussed.


"The El Greco fallacy" fallacy.
To what extent does an artist's work represent his or her perceptual world, and to what extent can attributes of his or her work be ascribed to sensory defects? These issues lie at the center of a conjecture more than a century old, which has been termed the El Greco fallacy. The El Greco fallacy posits that the elongation evident in El Greco's art reflects an underlying perceptual elongation of objects caused by astigmatism. The "logical" refutation of this theory argues that any perceptual elongation that El Greco might have experienced as a result of astigmatism would have caused not only his subjects to be elongated but also his canvas. Hence, it should have been unnecessary for him to elongate his paintings to match his perception. This objection is important because it warns us against drawing the erroneous conclusion that an artist's work represents a facsimile of his or her perception. However, an analysis of the effects of astigmatism on the retinal image suggests that this "logical" refutation of the El Greco fallacy promulgates another fallacy--that of astigmatism as a source of a constant perceptual error.


IL-1beta-mediated innate immunity is amplified in the db/db mouse model of type 2 diabetes.
Chronic inflammation appears to play a critical role in type 2 diabetes and its complications. Here we tested the hypothesis that this inflammatory dysregulation affects the IL-1beta system and has functional consequences in the brain. Diabetic, db/db, and nondiabetic, db/+, mice were administered i.p. LPS, a potent cytokine inducer, at a dose of 100 microg/kg/mouse. db/db mouse innate immune-associated sickness behavior was 14.8, 33, 44.7, and 34% greater than that of db/+ mice at 2, 4, 8, and 12 h, respectively. When a fixed dose of LPS was used (5 microg/mouse), db/db mouse sickness was again enhanced 18.4, 22.2, and 14.5% at 4, 8, and 12 h as compared with db/+ mice. In diabetic mice, peritoneal macrophages produced more IL-1beta in response to LPS, and peritoneal levels of IL-1beta induced by LPS were increased. Importantly, IL-1R antagonist and type 2 IL-1 receptor (IL-1R2) failed to up-regulate in response to LPS in db/db mice. Finally, both peripheral and central administration of IL-1beta, itself, induced sickness in db/db mice that mimicked the effects of peripheral LPS and was significantly greater than that seen in db/+ mice. Taken together, these results indicate that IL-1beta-mediated innate immunity is augmented in db/db mice both at the periphery and in the brain, and the mechanism is due to diabetes-associated loss of IL-1beta counterregulation.


Tailoring atomic layer growth at the liquid-metal interface.
Engineering atomic structures at metal surfaces represents an important step in the development of novel nanomaterials and nanodevices, but relies predominantly on atomic/molecular beam epitaxy under ultrahigh vacuum conditions, where controlling the deposition processes remains challenging. By using solution-borne nanosized gold clusters as a precursor, here we develop a wet deposition protocol to the fabrication of atomically flat gold nanoislands, so as to utilize the dynamic exchange of surface-active molecules at the liquid-metal interface for manipulating the growth kinetics of ultrathin metallic nanostructures. While remarkable shape and size selection of gold nanoislands is observed, our experimental and theoretical investigations provide compelling evidences that organic adsorbates can impart a bias to the island orientation by preferred adsorption and alignment and intervene in the assembly and disassembly of adatom islands by complexing with Au adatoms. This approach offers a simple solution to regulate atomic layer growth of metals at ambient conditions.


Toxoplasma gondii infection in cancer patients: prevalence, risk factors, genotypes and association with clinical diagnosis.
Prevalence of human infection with Toxoplasma gondii has been increasing in China due to the increasing number of cats. However, little is known of the epidemiology of T. gondii infection in different cancer patient groups. Thus, a case-control study of 900 cancer patients and 900 controls was conducted to detect anti-T. gondii antibodies by ELISA in China. Genomic DNA was extracted from the diseased tissues of 510 patients and the T. gondii B1 gene was amplified using a semi-nested PCR. DNA samples giving positive B1 amplification were then genetically characterized using multi-locus PCR-RFLP. The prevalence of anti-T. gondii IgG in cancer patients (35.56%) was significantly higher than that in controls (17.44%). The highest T. gondii seroprevalence was detected in lung cancer patients (60.94%), followed by cervical cancer patients (50%), brain cancer patients (42.31%) and endometrial cancer patients (41.67%). Exposure with soil and consumption of raw/undercooked meat were significantly associated with T. gondii infection in cancer patients. Three T. gondii genotypes (ToxoDB#9, ToxoDB#10 and Type I variant) were identified. In conclusion, T. gondii infection is a severe problem in cancer patients and it is imperative that improved integrated measures should be conducted to prevent and control T. gondii infection in cancer patients.