Combining cell-based hydrodynamics with hybrid particle-field simulations: efficient and realistic simulation of structuring dynamics.
We have extended an existing hybrid MD-SCF simulation technique that employs a coarsening step to enhance the computational efficiency of evaluating non-bonded particle interactions. This technique is conceptually equivalent to the single chain in mean-field (SCMF) method in polymer physics, in the sense that non-bonded interactions are derived from the non-ideal chemical potential in self-consistent field (SCF) theory, after a particle-to-field projection. In contrast to SCMF, however, MD-SCF evolves particle coordinates by the usual Newton's equation of motion. Since collisions are seriously affected by the softening of non-bonded interactions that originates from their evaluation at the coarser continuum level, we have devised a way to reinsert the effect of collisions on the structural evolution. Merging MD-SCF with multi-particle collision dynamics (MPCD), we mimic particle collisions at the level of computational cells and at the same time properly account for the momentum transfer that is important for a realistic system evolution. The resulting hybrid MD-SCF/MPCD method was validated for a particular coarse-grained model of phospholipids in aqueous solution, against reference full-particle simulations and the original MD-SCF model. We additionally implemented and tested an alternative and more isotropic finite difference gradient. Our results show that efficiency is improved by merging MD-SCF with MPCD, as properly accounting for hydrodynamic interactions considerably speeds up the phase separation dynamics, with negligible additional computational costs compared to efficient MD-SCF. This new method enables realistic simulations of large-scale systems that are needed to investigate the applications of self-assembled structures of lipids in nanotechnologies.


Sensitivity to viewpoint in children's drawings of objects and relations between objects.
Previous literature suggests that young children are relatively insensitive to viewpoint, only showing their view when the task is manipulated to provoke it. In contrast, older children appear to become more sensitive to viewpoint and it has been claimed that there is a developmental progression toward use of linear perspective as a means of drawing a view-specific scene. This study investigates sensitivity to viewpoint by manipulating it directly. Children between the ages of 6 and 14 years were asked to draw an L-shaped array of three cubes from one of three views: frontal eye level, frontal looking down, and corner looking down. At every age children showed sensitivity to their view in the sense that there were consistent differences between the drawings produced in the three viewing conditions. In the case of younger children this did not lead to an accurate portrayal of either their view or the array relations. Older children portrayed their view and the array relations more accurately, and viewpoint had a strong effect on the choice of projection system both within and between objects. There was no evidence of a general progression toward use of linear perspective.


Point mutation of Hoxd12 in mice.
Genes of the HoxD cluster play a major role in vertebrate limb development, and changes that modify the Hoxd12 locus affect other genes also, suggesting that HoxD function is coordinated by a control mechanism involving multiple genes during limb morphogenesis. In this study, mutant phenotypes were produced by treatment of mice with a chemical mutagen, N-ethyl-N-nitrosourea (ENU). We analyzed mutant mice exhibiting the specific microdactyly phenotype and examined the genes affected. We focused on phenotype characteristics including size, bone formation, and digit morphology of ENU-induced microdactyly mice. The expressions of several molecules were analyzed by genome-wide screening and quantitative real-time PCR to define the affected genes. We report on limb phenotypes of an ENU-induced A-to-C mutation in the Hoxd12 gene, resulting in alanine-to-serine conversion. Microdactyly mice exhibited growth defects in the zeugopod and autopod, shortening of digits, a missing tip of digit I, limb growth affected, and dramatic increases in the expressions of Fgf4 and Lmx1b. However, the expression level of Shh was not changed in Hoxd12 point mutated mice. These results suggest that point mutation rather than the entire deletion of Hoxd12, such as in knockout and transgenic mice, causes the abnormal limb phenotype in microdactyly mice. The precise nature of the spectrum of differences requires further investigation.


Emergence of a substrate-temperature-dependent dielectric process in a prototypical vapor deposited hole-transport glass.
Since the discovery of ultrastability, vapor deposition has emerged as a relevant tool to further understand the nature of glasses. By this route, the density and average orientation of glasses can be tuned by selecting the proper deposition conditions. Dielectric spectroscopy, on the other hand, is a basic technique to study the properties of glasses at a molecular level, probing the dynamics of dipoles or charge carriers. Here, and for the first time, we explore the dielectric behavior of vapor deposited N,N-Diphenyl-N,N'bis(methylphenyl)-1,1'-biphenyl-4,4'-diamines (TPD), a prototypical hole-transport material, prepared at different deposition temperatures. We report the emergence of a new relaxation process which is not present in the ordinary glass. We associate this process to the Maxwell-Wagner polarization observed in heterogeneous systems, and induced by the enhanced mobility of charge carriers in the more ordered vapor deposited glasses. Furthermore, the associated activation energy establishes a clear distinction between two families of glasses, depending on the selected substrate-temperature range. This finding positions dielectric spectroscopy as a unique tool to investigate the structural and electronic properties of charge transport materials and remarks the importance of controlling the deposition conditions, historically forgotten in the preparation of optoelectronic devices.


Involvement of increased endogenous asymmetric dimethylarginine in the hepatic endoplasmic reticulum stress of type 2 diabetic rats.
Increasing evidence suggested that endoplasmic reticulum (ER) stress contributes to insulin resistance, which plays an important role in the development of type 2 diabetes mellitus (T2DM). Accumulation of endogenous nitric oxide synthase (NOS) inhibitor, asymmetric dimethylarginine (ADMA), is associated with insulin resistance, T2DM, and diabetic cardiovascular complications, although the mechanisms have not been elucidated. This study was to determine whether elevated endogenous ADMA is involved in hepatic ER stress of type 2 diabetic rats, verify their causal relationship, and elucidate the potential mechanism underlying ADMA induced ER stress in rat hepatocytes. Immunoglobulin binding protein (Bip) transcription, eukaryotic initiation factor 2α kinase (eIF2α) phosphorylation, X box-binding protein-1 (XBP-1) mRNA splicing and C/EBP homologues protein (CHOP) expression were measured to reflect ER stress. Contents of ADMA and nitrite/nitrate as well as activities or expression of NOS and dimethylarginine dimethylaminohydrolase (DDAH) were detected to show the changes in DDAH/ADMA/NOS/NO pathway. The lipid peroxidation product malondialdehyde content and antioxidant enzyme superoxide dismutase activity were analyzed to evaluate oxidative stress. ER stress was provoked in the liver of type 2 diabetic rats, as expressed by increases of Bip transcription, eIF2α phosphorylation, XBP-1 splicing and CHOP expression, all of which were in parallel with the elevation of serum ADMA, suppression of NO generation, NOS and DDAH activities in the liver. Exposure of hepatocytes to ADMA or hydrogen peroxide also induced ER stress, which was associated with the inhibition of NO production and increase of oxidative stress. Treatment of hepatocytes with antioxidant pyrrolidine dithiocarbamate not only decreased ADMA-induced oxidative stress and inhibition of NO production but also reduced ADMA-triggered ER stress. These results indicate that increased endogenous ADMA contributes to hepatic ER stress in type 2 diabetic rats, and the mechanism underlying ADMA-induced ER stress may relate to oxidative stress via NOS uncoupling.


Biphasic Ca2+ dependence of inositol 1,4,5-trisphosphate-induced Ca release in smooth muscle cells of the guinea pig taenia caeci.
Ca2+ dependence of the inositol 1,4,5-trisphosphate (IP3)-induced Ca release was studied in saponin-skinned smooth muscle fiber bundles of the guinea pig taenia caeci at 20-22 degrees C. Ca release from the skinned fiber bundles was monitored by microfluorometry of fura-2. Fiber bundles were first treated with 30 microM ryanodine for 120 s in the presence of 45 mM caffeine to lock open the Ca-induced Ca release channels which are present in approximately 40% of the Ca store of the smooth muscle cells of the taenia. The Ca store with the Ca-induced Ca release mechanism was functionally removed by this treatment, but the rest of the store, which was devoid of the ryanodine-sensitive Ca release mechanism, remained intact. The Ca2+ dependence of the IP3-induced Ca release mechanism was, therefore, studied independently of the Ca-induced Ca release. The rate of IP3-induced Ca release was enhanced by Ca2+ between 0 and 300 nM, but further increase in the Ca2+ concentration also exerted an inhibitory effect. Thus, the rate of IP3-induced Ca release was about the same in the absence of Ca2+ and at 3 microM Ca2+, and was about six times faster at 300 nM Ca2+. Hydrolysis of IP3 within the skinned fiber bundles was not responsible for these effects, because essentially the same effects were observed with or without Mg2+, an absolute requirement of the IP3 phosphatase activity. Ca2+, therefore, is likely to affect the gating mechanism and/or affinity for the ligand of the IP3-induced Ca release mechanism. The biphasic effect of Ca2+ on the IP3-induced Ca release is expected to form a positive feedback loop in the IP3-induced Ca mobilization below 300 nM Ca2+, and a negative feedback loop above 300 nM Ca2+.


Oral budesonide for active Crohn's disease. Canadian Inflammatory Bowel Disease Study Group.
Corticosteroids are the most efficacious drugs for inducing remission in active Crohn's disease, but their benefits are frequently offset by serious side effects. Budesonide is a corticosteroid with high topical antiinflammatory activity but low systemic activity because of extensive hepatic metabolism. We investigated the efficacy and safety of an oral controlled-ileal-release preparation of budesonide in patients with active Crohn's disease involving the ileum or ileum and proximal colon. In a double-blind, multicenter trial, 258 patients were randomly assigned to receive placebo or one of three doses of budesonide--3, 9, or 15 mg daily. The primary outcome measure was clinical remission, as defined by a score of 150 or less on the Crohn's disease activity index. After eight weeks of treatment, remission occurred in 51 percent of the patients in the group receiving 9 mg of budesonide (95 percent confidence interval, 39 to 63 percent), 43 percent of those receiving 15 mg (95 percent confidence interval, 31 to 55 percent), and 33 percent of those receiving 3 mg (95 percent confidence interval, 21 to 44 percent), as compared with 20 percent of those receiving placebo (P < 0.001, P = 0.009, and P = 0.13, respectively). Improvements in the quality of life, as measured by the patients' responses to the inflammatory bowel disease questionnaire, paralleled these remission rates. Location of disease, prior surgical resection, and previous use of corticosteroids did not affect the outcome. A total of 119 patients (46 percent) were withdrawn from the study before the trial ended, 96 because of insufficient therapeutic effects, 13 because of adverse reactions, and 10 because of noncompliance. Budesonide caused a dose-related reduction in basal and corticotropin-stimulated plasma cortisol concentrations but was not associated with clinically important corticosteroid-related symptoms or other toxic effects. In an eight-week trial, an oral controlled-release preparation of budesonide at an optimal daily dose of 9 mg was well tolerated and effective against active Crohn's disease of the ileum and proximal colon.


Ultra thin hydro-films based on lactose-crosslinked fish gelatin for wound healing applications.
This study focuses on the development and characterization of an ultra thin hydro-film based on lactose-mediated crosslinking of fish gelatin by Maillard reaction. Lactose results in the only efficient crosslinker able to produce resistant to handling hydro-films when compared to conventional crosslinkers such as glutaraldehyde or genipin (tested at 25 and 37°C in phosphate buffer saline solution (PBS)).The disappearance of the peak related to the N-containing groups (XPS) and the images obtained by SEM and AFM demonstrate the highly ordered nano-scaled structure of lactose-crosslinked gelatin, confirming the crosslinking efficiency. This dressing presents high hydrophilicity and mild occlusivity, as shown by the swelling curve (max swelling at 5min) and by the occlusion factor of 25.17±0.99%, respectively. It demonstrates high stability to hydrolysis or cell-mediated degradation. Moreover, ISO 10993-5:2009 biocompatibility assay results in undetectable cytotoxicity effects. Spreading, adhesion and proliferation assays confirm the excellent adaptability of the cells onto the hydro-film surface without invading the dressing. Finally, the hydro-film enables the controlled delivery of therapeutic factors, such as the epidermal growth factor (EGF). This study demonstrates that lactose-mediated crosslinking is able to produce ultra thin gelatin hydro-films with suitable properties for biomedical applications, such as wound healing.


Doctors' knowledge of the appropriate use and route of administration of antidotes in the management of recreational drug toxicity.
Specific antidotes (eg, naloxone, flumazenil, cyproheptadine and benzodiazepines) are available for the management of certain recreational drug-induced toxicities. Some controversies surround the use of some of these antidotes, especially flumazenil in benzodiazepine toxicity. There are no previously published data on doctors' knowledge of the use of these specific antidotes. A questionnaire survey was designed to determine internal/emergency medicine doctors' knowledge of the appropriate use of antidotes in the management of clinical scenarios of acutely poisoned patients. For nine simulated clinical scenarios of acute toxicity from recreational drugs (benzodiazepines, cocaine, N-methyl-L-(3,4-methylene-dioxyphenyl)-2-aminopropane (MDMA)-induced serotonin toxicity and opioids), they were asked to indicate whether the suggested antidote and route of administration were correct. 42 physicians of all grades completed the questionnaire. The mean correct score was 5.4 (SD 1.1) (median 6, interquartile range 5-7). The percentages correct for the various clinical scenarios were 68.3% for opioid toxicity, 81% for benzodiazepine toxicity, 28.6% for MDMA-induced serotonin toxicity and 70.2% for cocaine toxicity. Doctors were more likely to record an answer of "unsure" for the use of cyproheptadine in ST serotonin toxicity (28.6%) compared with the use of the other antidotes (1.4%; p<0.001). Knowledge of the appropriate use of antidotes in recreational drug toxicity is not consistent, with poorer knowledge on the use of newer antidotes such as cyproheptadine in serotonin toxicity. Education is required both to increase overall knowledge on the use of specific antidotes in the management of recreational drug-induced toxicity, as well as focusing on newer antidotes such as cyproheptadine.


Marketing HPV vaccine: implications for adolescent health and medical professionalism.
The new vaccine against 4 types of human papillomavirus (HPV), Gardasil, like other immunizations appears to be a cost-effective intervention with the potential to enhance both adolescent health and the quality of their adult lives. However, the messages and the methods by which the vaccine was marketed present important challenges to physician practice and medical professionalism. By making the vaccine's target disease cervical cancer, the sexual transmission of HPV was minimized, the threat of cervical cancer to adolescents was maximized, and the subpopulations most at risk practically ignored. The vaccine manufacturer also provided educational grants to professional medical associations (PMAs) concerned with adolescent and women's health and oncology. The funding encouraged many PMAs to create educational programs and product-specific speakers' bureaus to promote vaccine use. However, much of the material did not address the full complexity of the issues surrounding the vaccine and did not provide balanced recommendations on risks and benefits. As important and appropriate as it is for PMAs to advocate for vaccination as a public good, their recommendations must be consistent with appropriate and cost-effective use.


Transcriptional coregulators in development.
Small differences in the levels of an extracellular signaling molecule can specify cell fate during development. Threshold responses are often determined at the level of transcription. Cell-specific and spatially localized patterns of gene expression depend on combinations of sequence-specific activators and repressors that bind to extensive cis-regulatory regions. Different mechanisms for integrating this complex regulatory information are discussed, particularly the role of coregulatory proteins, which are recruited to the DNA template by sequence-specific transcription factors. Recent studies suggest that a growing set of coactivators and corepressors mediate communication between diverse upstream regulatory proteins and the core RNA polymerase II transcription complex.


The qualitative similarity hypothesis: research synthesis and future directions.
In the penultimate article of a two-part special issue of the American Annals of the Deaf examining the qualitative similarity hypothesis (QSH), findings of nine research teams with articles in the special issue are summarized. The teams addressed three questions: (a) For students who are d/Deaf or hard of hearing (d/Dhh), is reading qualitatively similar to the reading process of hearing students (per the QSH)? (b) Is it, rather, qualitatively different (per the qualitative difference hypothesis [QDH])? (c) Or is reading qualitatively similar and qualitatively different? All nine teams recognized that aspects of the reading acquisition process of d/Dhh children resemble those of hearing children and that the QSH is tenable if it is independent of a child's language modality. Two teams concluded that there is research supporting both the QSH and the QDH. Implications for teacher education, future research, and language policymaking are discussed.


Chronic obstructive pulmonary disease surveillance--United States, 1971-2000.
Chronic obstructive pulmonary disease (COPD) includes chronic bronchitis and emphysema but has been defined recently as the physiologic finding of nonreversible pulmonary function impairment. This surveillance summary reports trends in different measures of COPD during 1971-2000. This report presents national data regarding objectively determined COPD (1971-1994); COPD-associated activity and functional limitations (1980-1996); self-reported COPD prevalence, COPD physician office and hospital outpatient department visits, COPD hospitalizations, and COPD deaths (1980-2000); and COPD emergency department visits (1992-2000). CDC's National Center for Health Statistics (NCHS) conducts the National Health Interview Survey annually, which includes questions concerning COPD and activity limitations. NCHS collects physician office-visit data in the National Ambulatory Medical Care Survey, emergency department and hospital outpatient department data in the National Hospital Ambulatory Medical Care Survey, hospitalization data in the National Hospital Discharge Survey, and death data in the Mortality Component of the National Vital Statistics System. Data regarding pulmonary function were obtained from the National Health and Nutrition Examination Surveys (NHANES) I (1971-1975) and III (1988-1994), and data regarding functional limitation were obtained from NHANES III, Phase 2 (1991-1994). During 2000, an estimated 10 million U.S. adults reported physician-diagnosed COPD. However, data from NHANES III estimate that approximately 24 million U.S. adults have evidence of impaired lung function, indicating that COPD is underdiagnosed. During 2000, COPD was responsible for 8 million physician office and hospital outpatient visits, 1.5 million emergency department visits, 726,000 hospitalizations, and 119,000 deaths. During the period analyzed, the most substantial changes was the increase in the COPD death rate for women, from 20.1/100,000 in 1980 to 56.7/100,000 in 2000, compared with the more modest increase in the death rate for men, from 73.0/100,000 in 1980 to 82.6/100,000 in 2000. In 2000, for the first time, the number of women dying from COPD surpassed the number of men dying from COPD (59,936 versus 59,118). Another substantial change observed is that the proportion of the population aged < 55 years with mild or moderate COPD, on the basis of pulmonary function testing, decreased from 1971-1975 to 1988-1994, possibly indicating that the upward trends in COPD hospitalizations and mortality might not continue. COPD is a major cause of morbidity, mortality, and disability in the United States. Despite its ease of diagnosis, COPD remains an underdiagnosed disease, chiefly in its milder and more treatable form.


Calcium Retrieval from Vacuolar Pools (Characterization of a Vacuolar Calcium Channel).
Voltage patch-clamp experiments at the whole-vacuole and single-channel levels were employed to study the retrieval of Ca2+ from vacuoles into the cytoplasm in sugar beet cell (Beta vulgaris L.) suspension cultures. Channels allowing the movement of Ca2+ out of the vacuole were identified at physiological conditions of pH, vacuolar membrane potential, and vacuole/cytoplasm Ca2+ concentrations. The operation of the channel was voltage dependent and inositol-1,4,5-triphosphate insensitive and displayed high selectivity for Ca2+ ions. These channels bear similarities to the dihydropyridine-sensitive L-type Ca2+ channels from animal cells. Bay K-8644, an agonist, increased the frequency of channel openings, whereas nifedipine, an antagonist, reduced the channel activity. Both effects were elicited only from the vacuolar side of the channel. Channel activities were also inhibited by verapamil, La3+, and cytoplasmic Ca2+ concentrations higher than 1 x 10-6 M. The modulation of the channel currents by cytoplasmic Ca2+ would suggest the role of these channels in triggering the initiation of signal transduction processes in plant cells.


Altered activities of transcription factors and their related gene expression in cardiac tissues of diabetic rats.
Gene regulation in the cardiovascular tissues of diabetic subjects has been reported to be altered. To examine abnormal activities in transcription factors as a possible cause of this altered gene regulation, we studied the activity of two redox-sensitive transcription factors--nuclear factor-kappaB (NF-kappaB) and activating protein-1 (AP-1)--and the change in the mRNA content of heme oxygenase-1, which is regulated by these transcription factors in the cardiac tissues of rats with streptozotocin-induced diabetes. Increased activity of NF-kappaB and AP-1 but not nuclear transcription-activating factor, as determined by an electrophoretic mobility shift assay, was found in the hearts of 4-week diabetic rats. Glycemic control by a subcutaneous injection of insulin prevented these diabetes-induced changes in transcription factor activity. In accordance with these changes, the mRNA content of heme oxygenase-1 was increased fourfold in 4-week diabetic rats and threefold in 24-week diabetic rats as compared with control rats (P < 0.01 and P < 0.05, respectively). Insulin treatment also consistently prevented changes in the mRNA content of heme oxygenase-1. The oral administration of an antioxidant, probucol, to these diabetic rats partially prevented the elevation of the activity of both NF-kappaB and AP-1, and normalized the mRNA content of heme oxygenase-1 without producing any change in the plasma glucose concentration. These results suggest that elevated oxidative stress is involved in the activation of the transcription factors NF-kappaB and AP-1 in the cardiac tissues of diabetic rats, and that these abnormal activities of transcription factors could be associated with the altered gene regulation observed in the cardiovascular tissues of diabetic rats.


Inertial cavitation to non-invasively trigger and monitor intratumoral release of drug from intravenously delivered liposomes.
The encapsulation of cytotoxic drugs within liposomes enhances pharmacokinetics and allows passive accumulation within tumors. However, liposomes designed to achieve good stability during the delivery phase often have compromised activity at the target site. This problem of inefficient and unpredictable drug release is compounded by the present lack of low-cost, non-invasive methods to measure such release. Here we show that focused ultrasound, used at pressures similar to those applied during diagnostic ultrasound scanning, can be utilised to both trigger and monitor release of payload from liposomes. Notably, drug release was influenced by liposome composition and the presence of SonoVue® microbubbles, which provided the nuclei for the initiation of an event known as inertial cavitation. In vitro studies demonstrated that liposomes formulated with a high proportion of 1,2 distearoyl-sn-glycero-3-phosphoethanolamine (DSPE) released up to 30% of payload following ultrasound exposure in the presence of SonoVue®, provided that the exposure created sufficient inertial cavitation events, as characterised by violent bubble collapse and the generation of broadband acoustic emissions. In contrast a 'Doxil'-like liposome formulation gave no such triggered release. In pre-clinical studies, ultrasound was used as a non-invasive, targeted stimulus to trigger a 16-fold increase in the level of payload release within tumors following intravenous delivery. The inertial cavitation events driving this release could be measured remotely in real-time and were a reliable predictor of drug release.


Platelet expression of stromal cell-derived factor-1 is associated with the degree of valvular aortic stenosis.
Platelet surface expression of stromal-cell-derived factor-1 (SDF-1) is increased during platelet activation and constitutes an important factor in hematopoetic progenitor cell trafficking at sites of vascular injury and ischemia. Enhanced platelet SDF-1 expression has been reported previously in patients suffering from acute coronary syndrome (ACS). We hypothesized that expression of platelet associated SDF-1 may also be influenced by calcified valvular aortic stenosis (AS). We consecutively evaluated 941 patients, who were admitted to the emergency department with dyspnea and chest pain. Platelet surface expression of SDF-1 was determined by flow cytometry, AS was assessed using echocardiography and hemodynamic assessment by heart catheterization. A 1∶1 propensity score matching was implemented to match 218 cases with 109 pairs adjusting for age, sex, cardiovascular risk factors, and medication including ACE inhibitors, angiotensin receptor blockers, beta blockers, statins, aspirin, clopidogrel, GPIIb/IIIa antagonists, and vitamin K antagonists. Patients with valvular AS showed enhanced platelet SDF-1 expression compared to patients without AS (non-valvular disease, NV) independent of ACS and stable coronary artery disease (SAP) [mean fluorescence intensity (MFI) for ACS (AS vs. NV): 75±40.4 vs. 39.5±23.3; P = 0.002; for SAP (AS vs. NV): 54.9±44.6 vs. 24.3±11.2; P = 0.008]. Moreover, the degree of AS significantly correlated with SDF-1 platelet surface expression (r = 0.462; P = 0.002). Valvular AS is associated with enhanced platelet-SDF-1 expression; moreover the degree of valvular AS correlates with SDF-1 platelet surface expression. These findings may have clinical implications in the future.


Predicting outcome after traumatic brain injury: development and validation of a prognostic score based on admission characteristics.
The early prediction of outcome after traumatic brain injury (TBI) is important for several purposes, but no prognostic models have yet been developed with proven generalizability across different settings. The objective of this study was to develop and validate prognostic models that use information available at admission to estimate 6-month outcome after severe or moderate TBI. To this end, this study evaluated mortality and unfavorable outcome, that is, death, and vegetative or severe disability on the Glasgow Outcome Scale (GOS), at 6 months post-injury. Prospectively collected data on 2269 patients from two multi-center clinical trials were used to develop prognostic models for each outcome with logistic regression analysis. We included seven predictive characteristics-age, motor score, pupillary reactivity, hypoxia, hypotension, computed tomography classification, and traumatic subarachnoid hemorrhage. The models were validated internally with bootstrapping techniques. External validity was determined in prospectively collected data from two relatively unselected surveys in Europe (n = 796) and in North America (n = 746). We evaluated the discriminative ability, that is, the ability to distinguish patients with different outcomes, with the area under the receiver operating characteristic curve (AUC). Further, we determined calibration, that is, agreement between predicted and observed outcome, with the Hosmer-Lemeshow goodness-of-fit test. The models discriminated well in the development population (AUC 0.78-0.80). External validity was even better (AUC 0.83-0.89). Calibration was less satisfactory, with poor external validity in the North American survey (p < 0.001). Especially, observed risks were higher than predicted for poor prognosis patients. A score chart was derived from the regression models to facilitate clinical application. Relatively simple prognostic models using baseline characteristics can accurately predict 6-month outcome in patients with severe or moderate TBI. The high discriminative ability indicates the potential of this model for classifying patients according to prognostic risk.


HuR Small-Molecule Inhibitor Elicits Differential Effects in Adenomatosis Polyposis and Colorectal Carcinogenesis.
HuR is an RNA-binding protein implicated in immune homeostasis and various cancers, including colorectal cancer. HuR binding to AU-rich elements within the 3' untranslated region of mRNAs encoding oncogenes, growth factors, and various cytokines leads message stability and translation. In this study, we evaluated HuR as a small-molecule target for preventing colorectal cancer in high-risk groups such as those with familial adenomatosis polyposis (FAP) or inflammatory bowel disease (IBD). In human specimens, levels of cytoplasmic HuR were increased in colonic epithelial cells from patients with IBD, IBD-cancer, FAP-adenoma, and colorectal cancer, but not in patients with IBD-dysplasia. Intraperitoneal injection of the HuR small-molecule inhibitor MS-444 in AOM/DSS mice, a model of IBD and inflammatory colon cancer, augmented DSS-induced weight loss and increased tumor multiplicity, size, and invasiveness. MS-444 treatment also abrogated tumor cell apoptosis and depleted tumor-associated eosinophils, accompanied by a decrease in IL18 and eotaxin-1. In contrast, HuR inhibition in APCMin mice, a model of FAP and colon cancer, diminished the number of small intestinal tumors generated. In this setting, fecal microbiota, evaluated by 16S rRNA gene amplicon sequencing, shifted to a state of reduced bacterial diversity, with an increased representation of Prevotella, Akkermansia, and Lachnospiraceae Taken together, our results indicate that HuR activation is an early event in FAP-adenoma but is not present in IBD-dysplasia. Furthermore, our results offer a preclinical proof of concept for HuR inhibition as an effective means of FAP chemoprevention, with caution advised in the setting of IBD. Cancer Res; 77(9); 2424-38. ©2017 AACR.


Usefulness of pulmonary vascular leakiness assessment in interstitial pneumonitis.
Pulmonary vascular leakiness of (67)Ga-circulating transferrin in interstitial pneumonitis (IP) was estimated by our previously described method, and its ability to evaluate disease activity was compared with conventional (67)Ga scintigraphy. Using 30-min dynamic scanning data after IV injection of (67)Ga citrate, the exponential equilibration coefficient of (67)Ga between the intravascular and pulmonary interstitial compartments was calculated and defined as the leak index (LI). Pulmonary (67)Ga uptake was assessed by gallium index, determined by conventional static images taken 48 h after (67)Ga citrate injection. Hospitalized patients. The study population consisted of 17 control patients and 20 patients with IP. The mean LI in patients with IP was significantly higher than in the control group (p < 0.0001), whereas no significant increase in gallium index was noted between the IP group and the control group. No significant correlation was found between gallium index and LI among all study participants. Mean LI in patients with active IP was significantly higher than in patients with stable IP (p = 0.0024). An increase in pulmonary vascular leakiness was found in patients with IP. LI may be useful to assess the disease activity.


An examination of referential and affect specificity with five emotions in infancy.
Referential specificity and affect specificity were examined in 12- to 14-month-olds (n=20), and 16- to 18-month-olds (n=20). Infants were presented with a televised social referencing paradigm involving an actress who emoted a simple descriptive message to one of two objects appearing on the video. The actress altered her affective message using a neutral baseline first, followed by 5 discrete emotions (anger, fear, sadness, happiness, surprise). Infants were given 30s to interact with the objects after watching the affective episode. Older infants demonstrated referential and affect specificity, as evidenced by their differential treatment of the target and distracter toy in response to messages of anger, fear, surprise, and happiness. In contrast, the younger infants did not show evidence of either referential or affect specificity, as evidenced by the lack of differentiation in their treatment of the target and distracter toy in response to positive and negative emotional messages across all emotional episodes.


Matrix metalloproteinases in cancer: from new functions to improved inhibition strategies.
Over the last years, the relevance of the matrix metalloproteinase (MMP) family in cancer research has grown considerably. These enzymes were initially associated with the invasive properties of tumour cells, owing to their ability to degrade all major protein components of the extracellular matrix (ECM) and basement membranes. However, further studies have demonstrated the implication of MMPs in early steps of tumour evolution, including stimulation of cell proliferation and modulation of angiogenesis. The establishment of causal relationships between MMP overproduction in tumour or stromal cells and cancer progression has prompted the development of clinical trials with a series of inhibitors designed to block the proteolytic activity of these enzymes. Unfortunately, the results derived from using broad-spectrum MMP inhibitors (MMPIs) for treating patients with advanced cancer have been disappointing in most cases. There are several putative explanations for the lack of success of these MMPIs including the recent finding that some MMPs may play a paradoxical protective role in tumour progression. These observations together with the identification of novel functions for MMPs in early stages of cancer have made necessary a reformulation of MMP inhibition strategies. A better understanding of the functional complexity of this proteolytic system and global approaches to identify the relevant MMPs which must be targeted in each individual cancer patient, will be necessary to clarify whether MMP inhibition may be part of future therapies against cancer.


Assessment of the clinical accuracy of serum and saliva assays for identification of adverse food reaction in dogs without clinical signs of disease.
To assess the clinical accuracy of 2 serum-based assays and 1 saliva-based assay for detection of adverse food reaction (AFR) in dogs without clinical signs of disease. 30 healthy client-owned dogs. Dog owners completed an online survey to collect comprehensive information about their pets' diet history. From each dog, serum and saliva samples were obtained and submitted for AFR testing by means of 3 assays that assessed the immunoglobulin response to 24 foods. Assays A and B measured food allergen-specific IgE concentrations in serum, whereas assay C measured food allergen-specific IgA and IgM concentrations in saliva. Descriptive data were generated, and Fisher exact tests were used to assess the respective associations between positive test results and specific food ingredients to which dogs were exposed. Assays A, B, and C yielded positive results for 26, 18, and 30 dogs, respectively. All dogs had positive results for at least 1 assay. The median (range) number of foods or ingredients to which dogs tested positive was 10.5 (0 to 24) for assay A, 1 (0 to 13) for assay B, and 12.5 (4 to 22; IgM) and 3 (0 to 24; IgA) for assay C. Positive test results were not significantly associated with prior food exposure. Saliva and serum assays for AFR often yielded positive results for apparently healthy dogs and are not recommended for clinical use. Elimination diet trials remain the gold standard for diagnosis of AFR in dogs.


The Comorbidity Burden of Hidradenitis Suppurativa in the United States: A Claims Data Analysis.
Prior studies have reported that hidradenitis suppurativa (HS) is accompanied by a myriad of physical and mental conditions. However, given the small sample sizes and the limited number of pre-selected comorbidities, these studies do not provide a complete picture of the comorbidity burden of HS in the USA. Moreover, the relationship between HS severity and comorbidity burden has yet to be characterized. Using a large US claims database, we estimated the comorbidity burden associated with HS, stratified by disease severity. A retrospective matched cohort design was used. Patients with HS were classified into two severity cohorts (milder and more severe) using an empirical algorithm based on treatments received. The comorbidity burden was compared between each HS cohort and their matched HS-free cohort, and between patients with milder vs. those with more severe forms of HS. Several physical and mental comorbidities were found to be more prevalent in both cohorts of patients with milder and more severe forms of HS than in their matched HS-free cohorts. The comorbidity burden also increased greatly as the disease progressed to more severe forms. The results of this study highlight the complexity of the comorbidity burden of HS patients and the need for a multidisciplinary approach to optimize the management of HS and its numerous associated comorbidities. AbbVie, Inc.


Antidepressants at environmentally relevant concentrations affect predator avoidance behavior of larval fathead minnows (Pimephales promelas).
The effects of embryonic and larval exposure to environmentally relevant (ng/L) concentrations of common antidepressants, fluoxetine, sertraline, venlafaxine, and bupropion (singularly and in mixture) on C-start escape behavior were evaluated in fathead minnows (Pimephales promelas). Embryos (postfertilization until hatching) were exposed for 5 d and, after hatching, were allowed to grow in control well water until 12 d old. Similarly, posthatch fathead minnows were exposed for 12 d to these compounds. High-speed (1,000 frames/s) video recordings of escape behavior were collected and transferred to National Institutes of Health Image for frame-by-frame analysis of latency periods, escape velocities, and total escape response (combination of latency period and escape velocity). When tested 12 d posthatch, fluoxetine and venlafaxine adversely affected C-start performance of larvae exposed as embryos. Conversely, larvae exposed for 12 d posthatch did not exhibit altered escape responses when exposed to fluoxetine but were affected by venlafaxine and bupropion exposure. Mixtures of these four antidepressant pharmaceuticals slowed predator avoidance behaviors in larval fathead minnows regardless of the exposure window. The direct impact of reduced C-start performance on survival and, ultimately, reproductive fitness provides an avenue to assess the ecological relevance of exposure in an assay of relatively short duration.


Temporally dissociated, trait-specific modifications underlie phenotypic polyphenism in Spea multiplicata tadpoles, which suggests modularity.
Many organisms that develop in a variable environment show correlated patterns of phenotypic plasticity in several traits. Any individual trait modification can be beneficial, neutral, or deleterious in any particular environment; the organism's total fitness, which determines if the plasticity is adaptive, is the sum of these changes. Although much is known about how plastic traits contribute to fitness, less is known about the extent to which the various trait changes involved in the plastic responses share their developmental control. Shared control suggests that the various responses evolved in unison, but independent control suggests independent evolution of many components. Spadefoot toads have evolved adaptive polyphenism to cope with developing in rapidly drying ephemeral ponds. Larvae hatch as omnivores, but on exposure to an environmental cue, may develop into carnivores. We compared trait development in the two morphs and found that differences in jaw musculature, head dimensions, and intestines emerged early in development, whereas differences in shape of the tail emerged later. In omnivores, all traits except intestine length and hind-limb length were negatively allometric with body length; in carnivores, two of three jaw muscles displayed positive allometry and, among those that were negatively allometric, all except head width showed larger allometric coefficients in carnivores. Hind-limb length was positively allometric in both forms, but the allometric coefficients did not differ significantly. Intestine length was positively allometric to body length in both forms, but in this case, omnivores exhibited the higher coefficient. These results suggest that spadefoot plasticity is trait specific and the responses are suggestive of the existence of at least two modules: a suite of trophic traits that responds early in development and a suite of tail traits that responds later. The developmental control of these suites is the subject of further investigation.


Anterior and posterior meniscofemoral ligaments: MRI evaluation.
Although meniscofemoral ligaments are distinct anatomic units, their anatomy and function are controversial from an anatomic and radiologic point of view. Five hundred knee MR examinations were retrospectively studied in an effort to demonstrate the incidence and variations regarding sex and age distribution, as well as the anatomy of the meniscofemoral ligament at magnetic resonance imaging. Patients were mostly men, three hundred and twelve, in contrast with women who were fewer, one hundred eighty-eight patients. The mean age of the patients who were included in this study was 46 years. More than half of them were between 20 and 40 years old; one hundred thirty-three patients among 20 to 30 years old and one hundred and one patients among 31 and 40 years old, in total two hundred thirty-four patients.


Trypsin cleavage in the COOH terminus of the bacteriophage T4 gene 41 DNA helicase alters the primase-helicase activities of the T4 replication complex in vitro.
The bacteriophage T4 gene 41 protein is a 5' to 3' DNA helicase which unwinds DNA ahead of the growing replication fork and, together with the T4 gene 61 protein, also functions as a primase to initiate DNA synthesis on the lagging strand. Proteolytic cleavage by trypsin approximately 20 amino acids from the COOH terminus of the 41 protein produces 41T, a 51,500-dalton fragment (possibly still associated with small COOH-terminal fragments) which still retains the ssDNA-stimulated GTPase (ATPase) activity, the 61 protein-stimulated DNA helicase activity, and the ability to act with 61 protein to synthesize pentaribonucleotide primers. In the absence of the T4 gene 32 ssDNA binding protein, the primase-helicase composed of the tryptic fragment (41T) and 61 proteins efficiently primes DNA synthesis on circular ssDNA templates by the T4 DNA polymerase and the three T4 polymerase accessory proteins. In contrast, the 41T protein is defective as a helicase or a primase component on 32 protein-covered DNA. Thus, unlike the intact protein, 41T does not support RNA-dependent DNA synthesis on 32 protein-covered ssDNA and does not stimulate strand displacement DNA synthesis on a nicked duplex DNA template. High concentrations of 32 protein strongly inhibit RNA primer synthesis with either 41 T or intact 41 protein. The 44/62 and 45 polymerase accessory proteins (and even the 44/62 proteins to some extent) substantially reverse the 32 protein inhibition of RNA primer synthesis with intact 41 protein but not with 41T protein. We propose that the COOH-terminal region of the 41 protein is required for its interaction with the T4 polymerase accessory proteins, permitting the synthesis and utilization of RNA primers and helicase function within the T4 replication complex. When this region is altered, as in 41T protein, the protein is unable to assemble a functional primase-helicase in the replication complex. An easy and rapid purification of T4 41 protein produced by a plasmid encoding this gene (Hinton, D. M., Silver, L. L., and Nossal, N. G. (1985) J. Biol. Chem. 260, 12851-12857) is also described.


Skinomics, transcriptional profiling approaches to molecular and structural biology of epidermis.
Skinomics is a field of bioinformatics applied specifically to skin biology and, by extension, to dermatology. Skinomics has been expanding into extensive genome-wide association studies, eg, of psoriasis, proteomics, lipidomics, metabolomics, metagenomics, and the studies of the microbiome. Here, the current state of the field of transcriptomics is reviewed, including the studies of the gene expression in human skin under several healthy and disease conditions. Specifically, transcriptional studies of epidermal differentiation, skin aging, effects of cytokines, inflammation with emphases on psoriasis and atopic dermatitis, and wound healing are reviewed. The transition from microarrays to NextGen sequencing is noted and potential future directions suggested.


Mirtron-mediated RNA knockdown/replacement therapy for the treatment of dominant retinitis pigmentosa.
Rhodopsin (RHO) gene mutations are a common cause of autosomal dominant retinitis pigmentosa (ADRP). The need to suppress toxic protein expression together with mutational heterogeneity pose challenges for treatment development. Mirtrons are atypical RNA interference effectors that are spliced from transcripts as short introns. Here, we develop a novel mirtron-based knockdown/replacement gene therapy for the mutation-independent treatment of RHO-related ADRP, and demonstrate efficacy in a relevant mammalian model. Splicing and potency of rhodopsin-targeting candidate mirtrons are initially determined, and a mirtron-resistant codon-modified version of the rhodopsin coding sequence is validated in vitro. These elements are then combined within a single adeno-associated virus (AAV) and delivered subretinally in a RhoP23H knock-in mouse model of ADRP. This results in significant mouse-to-human rhodopsin RNA replacement and is associated with a slowing of retinal degeneration. This provides proof of principle that synthetic mirtrons delivered by AAV are capable of reducing disease severity in vivo.


B-Cell Lymphoma 6 (BCL6) Is a Host Restriction Factor That Can Suppress HBV Gene Expression and Modulate Immune Responses.
Hepatitis B virus (HBV) infection causes acute and chronic liver inflammation. Recent studies have demonstrated that some viral antigens can suppress host innate and adaptive immunity, and thus lead to HBV liver persistency. However, the cellular factors that can help host cells to clear HBV during acute infection remain largely unknown. Here, we used HBV-cleared and HBV-persistent mouse models to seek for cellular factors that might participate in HBV clearance. HBV replicon DNA was delivered into the mouse liver by hydrodynamic injection. RNA-Seq analysis was conducted to identify immune-related genes that were differentially expressed in HBV-persistent and HBV-cleared mouse models. A cellular factor, B cell lymphoma 6 (BCL6), was found to be significantly upregulated in the liver of HBV-cleared mice upon HBV clearance. Co-expression of BCL6 and a persistent HBV clone rendered the clone largely cleared, implicating an important role of BCL6 in controlling HBV clearance. Mechanistic studies demonstrated that BCL6 functioned as a repressor, binding to and suppressing the activities of the four HBV promoters. Correspondingly, BCL6 expression significantly reduced the levels of HBV viral RNA, DNA, and proteins. BCL6 expression could be stimulated by inflammatory cytokines such as TNF-α; the BCL6 in turn synergized TNF-α signaling to produce large amounts of CXCL9 and CXCL10, leading to increased infiltrating immune cells and elevated cytokine levels in the liver. Thus, positive feedback loops on BCL6 expression and immune responses could be produced. Together, our results demonstrate that BCL6 is a novel host restriction factor that exerts both anti-HBV and immunomodulatory activities. Induction of BCL6 in the liver may ultimately assist host immune responses to clear HBV.


Fragments and dust after Holmium laser lithotripsy with or without "Moses technology": How are they different?
Urinary stones can be readily disintegrated by Holmium:YAG laser (Holmium laser lithotripsy), resulting in a mixture of small stone dust particles, which will spontaneously evacuate with urine and larger residual fragments (RF) requiring mechanical retrieval. Differences between fragments and dust have not been well characterized. Also, it remains unknown how the recently introduced "Moses technology" may alter stone disintegration products. Three complementary analytical techniques have been used in this study to offer an in-depth characterization of disintegration products after in vitro Holmium laser lithotripsy: stereoscopic microscopy, scanning electron microscopy and Fourier-transform infrared spectroscopy. Dust was separated from fragments based on its floating ability in saline irrigation. Depending on initial crystalline constituents, stone dust either conserved attributes found in larger RFs or showed changes in crystalline organization. These included conversion of calcium oxalate dihydrate towards calcium oxalate monohydrate, changes in carbapatite spectra towards an amorphous phase, changes of magnesium ammonium phosphate towards a differing amorphous and crystalline phase and the appearance of hydroxyapatite on brushite fragments. Comparatively, "Moses technology" produced more pronounced changes. These findings provide new insights suggesting a photothermal effect occurring in Holmium laser lithotripsy. Figure: Appearance of hydroxyapatite hexagons on stone dust collected after Holmium laser lithotripsy of a brushite stone using "Moses technology."


Symmetry breaking in development and stochastic gene expression.
The prevailing emphasis in developmental biology since the expansion of the molecular biology age has been that developmental decisions are instructive. A cell differentiates to become a specific cell type because it receives a signal, whereas its neighbor that does not receive the signal adopts a different fate. This emphasis has been generally accepted, largely because of the success of this view in tractable invertebrate model organisms, and the widespread similarities in molecular regulation to the development of more complex species. An alternative emphasis, that cells make their own decisions, has until the past decade been conspicuously silent. Here I trace the re-emergence of our appreciation of single cell decision-making in development, and how widespread this phenomenon is likely to be. I will focus the discussion on the potential role of stochastic gene expression in generating differences between cells in the absence of simple instructive signals and highlight the complexity of systems proposed to involve this type of regulation. Finally, I will discuss the approaches required to fully test hypotheses that noisy gene regulation can be extrapolated through developmental time to accurately specify cell fate. WIREs Dev Biol 2017, 6:e284. doi: 10.1002/wdev.284 For further resources related to this article, please visit the WIREs website.


Derived neutrophil to lymphocyte ratio as a prognostic factor in patients with advanced colorectal cancer according to RAS and BRAF status: a post-hoc analysis of the MRC COIN study.
The phase III Continuous or Intermittent (COIN) trial failed to show a benefit in overall survival (OS) of cetuximab in combination with chemotherapy for patients with metastatic colorectal cancer. High derived neutrophil to lymphocyte ratio (dNLR) has been shown to be prognostic in patients with metastatic colorectal cancer. The aim of this analysis is to evaluate dNLR as a predictive biomarker of the survival according to RAS and BRAF mutations status within the COIN trial. A post-hoc exploratory analysis of the COIN trial arms A and B was carried out. All patients with available white blood cell and neutrophil data were analysed. The dNLR was calculated using a formula that has previously shown predictive power in cancer patients: dNLR=ANC/(WBC-ANC). A high dNLR was defined as a value of 2.2 or more. dNLR was correlated with clinical outcomes using Kaplan-Meier and Cox regression analysis. A total of 1603 patients were assigned to the oxaliplatin-based chemotherapy (arm A, N=815) or oxaliplatin-based chemotherapy plus cetuximab (arm B, N=815) arms. There was a strong association between dNLR level and overall survival (OS) using Kaplan-Meier analysis. In all mutation groups, dNLR less than 2.2 was associated with better OS compared to dNLR of 2.2 or more. The median OS in patients with wild-type disease (dNLR<2.2 vs. dNLR≥2.2) was 22.8 versus 13.1 months [hazard ratio (HR)=1.33]; 16.9 versus 11.8 months (HR=1.36) in patients with RAS mutant tumours; and 12.6 versus 6.8 months (HR=1.67) in patients with BRAF mutant tumours. In patients with dNLR less than 2.2, the median OS was 19.2 months in arm A compared to 18.0 months in arm B (HR=1.11). Among patients with dNLR greater than or equal to 2.2, the median OS was 13.0 months in arm A compared with 13.1 months in arm B (HR=0.96). dNLR is strongly prognostic for survival in all mutation groups. dNLR does not predict for benefit from the addition of cetuximab.


PINCH expression in relation to radiation response in co-cultured colon cancer cells and in rectal cancer patients.
Particularly interesting new cysteine-histidine rich protein (PINCH), involved in cell spreading, motility and proliferation, has been shown to enhance radioresistance in colon cancer cell lines. The expression of PINCH in relation to radiation was studied in co-cultured colon cancer cells. Furthermore, the clinical significance between PINCH and radiotherapy (RT) was analyzed in rectal cancer patients with or without RT. The relative PINCH expression in colon cancer (KM12C) cells cultured separately and in co-culture was examined by western blotting and real-time PCR, and was analyzed over a period of 8 and 24 h after radiation. PINCH expression was immunohistochemically examined in 137 primary rectal tumors for which 65 cases did not receive RT and 72 cases received RT. PINCH expression tended to decrease from that in the separately cultured KM12C cells without radiation to that in cells with radiation at 8 h (P=0.060); while in the co-cultured cells, no significant difference was found (P=0.446). In patients with RT, strong PINCH expression was related to worse survival, when compared to patients with weak expression, independent of TNM stage, degree of differentiation, age and p53 status (P=0.029, RR 4.03, 95% CI 1.34‑12.1). No survival relationship for the patients without RT was observed (P=0.287). A statistical interaction analysis between PINCH, RT and survival showed a trend towards significance (P=0.057). In conclusion, PINCH predicts survival in rectal cancer patients with RT, but not in patients without RT. The expression of PINCH may be regulated by radiation and by environmental factors surrounding the cells.


Cardiometabolic Health in Adults Born Premature With Extremely Low Birth Weight.
Young adults born with extreme prematurity have increased blood pressure and insulin resistance. This study documents their metabolic health as they enter their fourth decade of life. The study objective was to compare body composition, glycemia, lipid levels, and blood pressure in adults born with extremely low birth weight (ELBW) versus age- and sex- matched normal birth weight (NBW) control subjects and to examine related previous and current exposures. The study examines one of the oldest regionally representative cohorts of ELBW subjects (birth weight <1 kg) and NBW individuals born between 1977 and 1982. The primary outcome was dysglycemia (type 2 diabetes or prediabetes) based on results of a 75-g oral glucose tolerance test. Secondary outcomes include body composition, insulin resistance, fasting lipid profile, and blood pressure. Potential predictive factors included birth weight, maternal antenatal corticosteroid exposure, retinopathy of prematurity, growth parameters, and smoking history. Adults (mean age, 31.8 years) born ELBW (n = 100) had a higher percent body fat (P = .004) and lower lean mass for height (P = .018) but similar waist circumference (P = .54) and BMI (P = .61) compared with NBW control subjects. ELBW adults had a 4.0-fold (95% confidence interval, 1.53-10.66) increased risk of developing dysglycemia. Adults born ELBW also had higher systolic (P = .004) and diastolic (P = .02) blood pressures compared with NBW control subjects, but there were no differences in lipid profile. By their fourth decade, these adults born extremely premature had increased body fat, lower lean mass, and a 4-fold increased risk of developing dysglycemia.


The Inhibitory Effects of Pentacyclic Triterpenes from Loquat Leaf against Th17 Differentiation.
Loquat leaf is an herb that is commonly used in traditional Chinese medicine (TCM) for its anti-inflammatory properties. Numerous studies have demonstrated that Th17 cells play a fundamental role in mediating SLE pathological deterioration. In our study, we investigated the inhibitory effect of pentacyclic triterpenes from loquat leaf on T helper 17 (Th17) cells and the therapeutic efficacy of OA in Lupus nephritis (LN) development. We isolated three pentacyclic triterpene compounds rom loquat leaf by bioassay-directed fractionation and separation method. There were methyl corosolate (MC), uvaol (UL), and oleanolic acid (OA) Firstly, we elucidated Retinoic acid receptor-related orphan receptor gamma t (RORγt) inhibitory activity of these three compounds in the cell-based assay and Th17 differentiation in vitro assay. Then, we used OA-treated pristine-induced LN mice to evaluate the therapeutic effects of OA in LN development. Anti-dsDNA level in serum was detected by enzyme-linked immunosorbent assay (ELISA), interleukin 17A (IL-17A) and interferon-γ (IFN-γ) expression in spleen cells by Flow cytometry (FCM), histomorphologic examination of kidneys were performed by periodic acid schiff (PAS) staining and immunofluorescence analysis. Pentacyclic triterpene compounds (MC, UL, OA) displayed inhibition of RORγt activity in cell-based assay and Th17 differentiation in vitro. Furthermore, our results also showed that OA could significantly decrease serum anti-dsDNA antibody levels, IL-17A and IFN-γ expression and alleviate renal pathological damage in OA-treated group mice than in the model group mice. These results demonstrated that OA can improve the clinical manifestation of LN, indicating potential application in SLE therapy.


Cross-cultural adaptation and psychometric assessment of the Turkish version of the Vulnerability to Abuse Screening Scale
Background/aim: The aim of this study was to evaluate the reliability and validity of the Turkish version of the Vulnerability to Abuse Screening Scale (VASS). Materials and methods: This was a methodological study. The sample included 140 elderly individuals. Data were collected by using a questionnaire form, the VASS, and the Geriatric Depression Scale (GDS). The Cronbach alpha value was calculated and test?retest reliability was tested for the reliability analyses. Results: The Cronbach alpha value calculated for the VASS (12 items) was 0.819. There was no difference between test and retest mean scores of the VASS. A statistically significantly positive and strong relationship was found between the test and retest scores of the individuals. A statistically significantly positive and moderate relationship was found between the VASS and GDS scores. Factor analysis revealed that a total of four factors accounted for 63.66% of the total variance with an eigenvalue of >1. These results show that the Turkish version of the VASS is a valid and reliable scale. Conclusion: This study showed that the adoption of the translated VASS in Turkey is reliable and valid to evaluate the risk of abuse in adults over the age of 65.


Imaging atherosclerosis with positron emission tomography.
Positron emission tomography (PET) provides a non-invasive method to measure biological processes that are relevant to atherosclerosis, including arterial inflammation and calcification. The vast majority of studies imaging atherosclerosis with PET have utilized the tracer 18F-fluorodeoxyglucose (FDG) to better understand how inflammation contributes to atherosclerosis development, and to test the efficacy of therapeutic interventions aimed at reducing its progression. Additional tracers such as 18F-sodium fluoride (18F-NaF) provide additional avenues for characterizing atherosclerosis development. This review examines the emerging uses of PET arterial imaging as a marker of vascular inflammation and atherosclerosis, as a prognostic tool, and as a clinical research tool. In addition, we examine emerging methods that should advance arterial imaging with PET.


Vascular access type and changes in inflammatory markers in incident dialysis patients: a pilot study.
To determine the association between the initial hemodialysis (HD) vascular access type and short-term changes in inflammation markers. This is a prospective, observational study in incident chronic kidney disease (CKD) (stages 4 and 5) patients receiving their first HD vascular access. Serum samples were obtained pre-access placement, and 1 week, and 1 month post-access insertion. Samples were tested for high sensitivity C-reactive protein (hsCRP) and interleukin-6 (IL-6) using ELISA. Patients with known inflammatory states (infection, malignancy, connective tissue disorders, organ transplantation and those on immune modulating agents) were excluded. The hsCRP and IL-6 values were transformed into logarithmic scale. Chi-square analysis, independent and paired t-tests were performed where appropriate, and a two-way ANOVA with time as a repeated measure was also performed. Significance was determined at p=0.05. One-month follow-up data was obtained in 48 patients (arteriovenous fistula (AVF), n=10; tunneled catheter (TC), n=28; arteriovenous graft (AVG), n=10). A significant increase in both hsCRP (p <0.05) and IL-6 (p=0.02) occurring 1 week after TC insertion was observed. Elevation of the IL-6 levels appeared to be sustained 1 month after TC insertion, although this finding was not statistically significant (p=0.68), whereas the hsCRP levels returned to baseline within 1 month. After AVG insertion only the hsCRP levels rose significantly (p=0.01) after 1 week and returned to baseline within 1 month. In the AVF group, inflammatory markers did not change for any time period. In CKD patients, TC and AVG insertion result in a transient state of inflammation 1 week post-operatively, which is not observed after AVF surgery. Whether this is a persistent phenomenon after TC insertion requires a larger, longitudinal study.


Temporal change analysis for characterization of mass lesions in mammography.
In this paper, we present a fully automated computer-aided diagnosis (CAD) program to detect temporal changes in mammographic masses between two consecutive screening rounds. The goal of this work was to improve the characterization of mass lesions by adding information about the tumor behavior over time. Towards this goal we previously developed a regional registration technique that finds for each mass lesion on the current view a location on the prior view where the mass was most likely to develop. For the task of interval change analysis, we designed two kinds of temporal features: difference features and similarity features. Difference features indicate the (relative) change in feature values determined on prior and current views. These features may be especially useful for lesions that are visible on both views. Similarity features measure whether two regions are comparable in appearance and may be useful for lesions that are visible on the prior view as well as for newly developing lesions. We evaluated the classification performance with and without the use of temporal features on a dataset consisting of 465 temporal mammogram pairs, 238 benign, and 227 malignant. We used cross validation to partition the dataset into a training set and a test set. The training set was used to train a support vector machine classifier and the test set to evaluate the classifier. The average A(z) value (area under the receiver operating characteristic curve) for classifying each lesion was 0.74 without temporal features and 0.77 with the use of temporal features. The improvement obtained by adding temporal features was statistically significant (P = 0.005). In particular, similarity features contributed to this improvement. Furthermore, we found that the improvement was comparable for masses that were visible and for masses that were not visible on the prior view. These results show that the use of temporal features is an effective approach to improve the characterization of masses.


The effect of contrast water therapy on symptoms of delayed onset muscle soreness.
This study examined the effect of contrast water therapy (CWT) on the physiological and functional symptoms of delayed onset muscle soreness (DOMS) following DOMS-inducing leg press exercise. Thirteen recreational athletes performed 2 experimental trials separated by 6 weeks in a randomized crossover design. On each occasion, subjects performed a DOMS-inducing leg press protocol consisting of 5 x 10 eccentric contractions (180 seconds recovery between sets) at 140% of 1 repetition maximum (1RM). This was followed by a 15-minute recovery period incorporating either CWT or no intervention, passive recovery (PAS). Creatine kinase concentration (CK), perceived pain, thigh volume, isometric squat strength, and weighted jump squat performance were measured prior to the eccentric exercise, immediately post recovery, and 24, 48, and 72 hours post recovery. Isometric force production was not reduced below baseline measures throughout the 72-hour data collection period following CWT ( approximately 4-10%). However, following PAS, isometric force production (mean +/- SD) was 14.8 +/- 11.4% below baseline immediately post recovery (p < 0.05), 20.8 +/- 15.6% 24 hours post recovery (p < 0.05), and 22.5 +/- 12.3% 48 hours post recovery (p < 0.05). Peak power produced during the jump squat was significantly reduced (p < 0.05) following both PAS (20.9 +/- 13.4%) and CWT (12.8 +/- 8.0%), with the mean reduction in power for PAS being marginally (not significantly) greater than for CWT (effect size = 0.76). Thigh volume measured immediately following CWT was significantly less than PAS. No significant differences in the changes in CK were found; in addition, there were no significant (p > 0.01) differences in perceived pain between treatments. Contrast water therapy was associated with a smaller reduction, and faster restoration, of strength and power measured by isometric force and jump squat production following DOMS-inducing leg press exercise when compared to PAS. Therefore, CWT seems to be effective in reducing and improving the recovery of functional deficiencies that result from DOMS, as opposed to passive recovery.


Outcome of induction and postremission therapy in younger adults with acute myeloid leukemia with normal karyotype: a cancer and leukemia group B study.
Evaluate the outcome of induction and postremission therapy in adults younger than 60 years with normal cytogenetics acute myeloid leukemia (AML). In 490 patients, induction included cytarabine and daunorubicin (AD) or cytarabine and escalated doses of daunorubicin and etoposide +/- PSC-833 (ADE/ADEP). Intensification included one cycle of high-dose cytarabine (HDAC) followed by etoposide/cyclophosphamide and mitoxantrone/diaziquone (group I), three HDAC cycles (group II), four intermediate-dose cytarabine (IDAC) or HDAC cycles (group III), or one HDAC/etoposide cycle and autologous stem-cell transplantation (ASCT; group IV). Of 350 patients receiving AD, 73% achieved complete remission (CR), compared with 82% of 140 receiving ADE/ADEP (P = .04). Splenomegaly was associated with a lower CR rate (P < .001), and ADE/ADEP, with a higher CR rate in younger patients (P = .005). The 5-year disease-free survival (DFS) rate was 28% each for intensification groups I and II, compared with 41% and 45% for groups III and IV, respectively (P = .02). The 5-year cumulative incidence of relapse (CIR) was 62% and 67% for groups I and II, respectively, compared with 54% and 44% for groups III and IV, respectively (P = .049). The type of postremission intensification remained significant for DFS and CIR in multivariable analysis. In younger adults with normal cytogenetics AML, splenomegaly predicts a lower CR rate, and the postremission strategies of either four cycles of I/HDAC or one cycle of HDAC/etoposide followed by ASCT are associated with improved DFS and reduced relapse compared with therapies that include fewer cycles of cytarabine or no transplantation.


Optimum nonlinear composite filter for distortion-tolerant pattern recognition.
We describe a nonlinear distortion-tolerant filter for pattern recognition that is optimum in terms of tolerance to input noise and discrimination capability. This filter was derived by minimization of the output energy that is due to the overlapping additive noise and the input scene, and the output of the filter meets the design constraints obtained from the training data set. The performance of this filter was tested with an input scene containing one of the training data sets, a nontraining true target, and a false object in the presence of overlapping additive noise and nonoverlapping background noise. We carried out Monte Carlo runs to measure the statistical performance of the filter and obtained receiver operating characteristics curves to show the detection capabilities of the filter.


Key biosynthetic gene subfamily recruited for pheromone production prior to the extensive radiation of Lepidoptera.
Moths have evolved highly successful mating systems, relying on species-specific mixtures of sex pheromone components for long-distance mate communication. Acyl-CoA desaturases are key enzymes in the biosynthesis of these compounds and to a large extent they account for the great diversity of pheromone structures in Lepidoptera. A novel desaturase gene subfamily that displays Delta11 catalytic activities has been highlighted to account for most of the unique pheromone signatures of the taxonomically advanced ditrysian species. To assess the mechanisms driving pheromone evolution, information is needed about the signalling machinery of primitive moths. The currant shoot borer, Lampronia capitella, is the sole reported primitive non-ditrysian moth known to use unsaturated fatty-acid derivatives as sex-pheromone. By combining biochemical and molecular approaches we elucidated the biosynthesis paths of its main pheromone component, the (Z,Z)-9,11-tetradecadien-1-ol and bring new insights into the time point of the recruitment of the key Delta11-desaturase gene subfamily in moth pheromone biosynthesis. The reconstructed evolutionary tree of desaturases evidenced two ditrysian-specific lineages (the Delta11 and Delta9 (18C>16C)) to have orthologs in the primitive moth L. capitella despite being absent in Diptera and other insect genomes. Four acyl-CoA desaturase cDNAs were isolated from the pheromone gland, three of which are related to Delta9-desaturases whereas the fourth cDNA clusters with Delta11-desaturases. We demonstrated that this transcript (Lca-KPVQ) exclusively accounts for both steps of desaturation involved in pheromone biosynthesis. This enzyme possesses a Z11-desaturase activity that allows transforming the palmitate precursor (C16:0) into (Z)-11-hexadecenoic acid and the (Z)-9-tetradecenoic acid into the conjugated intermediate (Z,Z)-9,11-tetradecadienoic acid. The involvement of a single Z11-desaturase in pheromone biosynthesis of a non-ditrysian moth species, supports that the duplication event leading to the origin of the Lepidoptera-specific Delta11-desaturase gene subfamily took place before radiation of ditrysian moths and their divergence from other heteroneuran lineages. Our findings uncover that this novel class of enzymes affords complex combinations of unique unsaturated fatty acyl-moieties of variable chain-lengths, regio- and stereo-specificities since early in moth history and contributes a notable innovation in the early evolution of moth-pheromones.


Molecular genetics of tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency.
Mutations in the phenylalanine hydroxylase (PAH) gene result in phenylketonuria (PKU). Tetrahydrobiopterin (BH(4))-responsive hyperphenylalaninemia has been recently described as a variant of PAH deficiency caused by specific mutations in the PAH gene. It has been suggested that BH(4)-responsiveness may be predicted from the corresponding genotypes. Data from BH(4) loading tests indicated an incidence of BH(4)-responsiveness of >40% in the general PKU population and >80% in mild PKU patients. The current project entailed genotype analysis of 315 BH(4)-responsive patients tabulated in the BIOPKUdb database and comparison with the data from the PAHdb locus-specific knowledgebase, as well as with previously published PAH mutations for several European countries, Northern China, and South Korea. We identified 57 mutations, presenting with a substantial residual PAH activity (average approximately 47%), presumed to be associated with BH(4)-responsiveness. More than 89% of patients are found to be compound heterozygotes. The three most common mutations found in >5% of BH(4)-responsive patients are p.A403 V, p.R261Q, and p.Y414C. Using the Hardy-Weinberg formula the predicted average frequency of BH(4)-responsiveness in European populations was calculated to be 55% (range 17-79%, lowest in Baltic countries and Poland and highest in Spain), 57% in Northern China, and 55% for South Korea. The genotype-predicted prevalence of BH(4)-responsiveness was higher than prevalence data obtained from BH(4) loading tests. Inconsistent results were observed for mutations p.L48S, p.I65 T, p.R158Q, p.R261Q, and p.Y414C. Our data suggest that BH(4)-responsiveness may be more common than assumed and to some extent may be predicted or excluded from the patient's genotype.


Tracing sources of sulfur in the Florida Everglades.
We examined concentrations and sulfur isotopic ratios (34S/32S, expressed as delta34S in parts per thousand [/1000] units) of sulfate in surface water, ground water, and rain water from sites throughout the northern Everglades to establish the sources of sulfur to the ecosystem. The geochemistry of sulfur is of particular interest in the Everglades because of its link, through processes mediated by sulfate-reducing bacteria, to the production of toxic methylmercury in this wetland ecosystem. Methylmercury, a neurotoxin that is bioaccumulated, has been found in high concentrations in freshwater fish from the Everglades, and poses a potential threat to fish-eating wildlife and to human health through fish consumption. Results show that surface water in large portions of the Everglades is heavily contaminated with sulfate, with the highest concentrations observed in canals and marsh areas receiving canal discharge. Spatial patterns in the range of concentrations and delta34S values of sulfate in surface water indicate that the major source of sulfate in sulfur-contaminated marshes is water from canals draining the Everglades Agricultural Area. Shallow ground water underlying the Everglades and rain water samples had much lower sulfate concentrations and delta34S values distinct from those found in surface water. The delta34S results implicate agricultural fertilizer as a major contributor to the sulfate contaminating the Everglades, but ground water under the Everglades Agricultural Area (EAA) may also be a contributing source. The contamination of the northern Everglades with sulfate from canal discharge may be a key factor in controlling the distribution and extent of methylmercury production in the Everglades.


Neutrophil-selective CD18 silencing using RNA interference in vivo.
Tissue-specific silencing of genes may be used for genetic engineering in mice and has possible therapeutic applications in humans. Current strategies in mice rely on Cre/loxP technology requiring the generation of multiple transgenic lines and breeding strategies. Here, we describe the selective silencing of CD18, a leukocyte-specific integrin in neutrophils using a micro RNA (miRNA) strategy that requires the generation of one transgenic line. CD18-specific miRNA hairpin driven by the myeloid specific human MRP8 promoter resulted in the generation of transgenic lines with 75% to 95% reduction in CD18 protein levels in neutrophils and monocytes. Minimal decreases in T cells and a partial diminution in macrophages were observed. Neutrophil CD18 silencing resulted in neutrophilia, splenomegaly, and significant defects in neutrophil trafficking with the degree of alterations correlating with the extent of CD18 silencing. Thus, our data demonstrate the utility of using miRNA approaches to silence genes in neutrophils, which are terminally differentiated cells with a short half-life that largely precludes their genetic manipulation in vitro. Furthermore, the mouse models provide a valuable tool to examine the contribution of CD18 on neutrophils to leukocyte adhesion deficiency type I (LAD-I), a complex inherited disorder in which reduced or absent CD18 expression in multiple leukocyte subsets leads to impaired innate and adaptive immune responses.


Cerebral Vasospasm Due to Arteriovenous Malformation-Associated Hemorrhage: Impact of Bleeding Source and Pattern.
Cerebral vasospasm (CVS) after a ruptured arteriovenous malformation (AVM) is rarely reported. This study is aimed at evaluating the predictive variables in AVM hemorrhage for CVS. A total of 160 patients with ruptured AVMs were admitted to our neurosurgical department from 2002 to 2018. The frequency of cerebral vasospasm after AVM hemorrhage and the impact of AVM-associated aneurysms were evaluated. We compared different bleeding patterns, such as intracerebral hemorrhage (ICH), subarachnoid hemorrhage (SAH) or a combination of both (ICH + SAH) and evaluated predictive variables for outcome in last follow-up. A total of 62 (39%) patients had AAA, mostly located prenidal (75.8%). AVMs with ruptured aneurysms often resulted in ICH with SAH component (p < 0.001). Eighty-two patients (51%) presented a SAH component, and CVS occurred in 6 patients (7.3%), mostly due to a ruptured infratentorial AVM (p < 0.03). Infratentorial location and the amount of SAH component (p < 0.001) predicted the incidence of CVS significantly. Cerebral infarction was significantly associated with CVS (p < 0.02). SAH component and infratentorial location of ruptured AVMs may harbor a higher risk for CVS. Follow-up with angiographic imaging should be considered in patients with infratentorial AVM hemorrhage and delayed neurologic deterioration to rule out CVS.


Three versions of Perceived Stress Scale: validation in a sample of Chinese cardiac patients who smoke.
Smoking causes heart disease, the major cause of death in China and Hong Kong. Stress is one major trigger of smoking and relapse, and understanding stress among smoking cardiac patients can therefore help in designing effective interventions to motivate them to quit. The objective of this study was to examine the psychometric properties of the Perceived Stress Scale (PSS), and to compare the appropriateness of the three versions of the scale (PSS-14, PSS-10, and PSS-4) among Chinese cardiac patients who were also smokers. From March 2002 to December 2004, 1860 cardiac patients who smoked were recruited at the cardiac outpatient clinics of ten acute hospitals in Hong Kong, and 1800 questionnaires were analysed. Participants completed a questionnaire including the PSS, nicotine dependence and certain demographic variables. The psychometric properties of the PSS were investigated: construct validity using confirmatory factor analysis, reliability using Cronbach's alpha and concurrent validity by examining the relationship with smoking- and health-related variables. For all the three versions of the PSS, confirmatory factor analyses corroborated the 2-factor structure of the scale, with the positive and negative factors correlating significantly and negatively to a moderate extent (r < -0.5), and high Cronbach's alpha values for the two subscales (alpha > 0.5). All the correlations of the two subscales and the smoking- and health-related variables were statistically significant and in the expected directions although of small magnitudes, except daily cigarette consumption. The findings confirmed the satisfactory psychometric properties of all three Chinese versions of PSS. We recommend the use of PSS-10 for research which focuses on the two components of perceived stress, as it shows a higher reliability; and the use of PSS-4 if such partition is not essential and space for multiple measures is limited.


Measurement of the traction force of biological cells by digital holography.
The traction force produced by biological cells has been visualized as distortions in flexible substrata. We have utilized quantitative phase microscopy by digital holography (DH-QPM) to study the wrinkling of a silicone rubber film by motile fibroblasts. Surface deformation and the cellular traction force have been measured from phase profiles in a direct and straightforward manner. DH-QPM is shown to provide highly efficient and versatile means for quantitatively analyzing cellular motility.


MOLIERE: Automatic Biomedical Hypothesis Generation System.
Hypothesis generation is becoming a crucial time-saving technique which allows biomedical researchers to quickly discover implicit connections between important concepts. Typically, these systems operate on domain-specific fractions of public medical data. MOLIERE, in contrast, utilizes information from over 24.5 million documents. At the heart of our approach lies a multi-modal and multi-relational network of biomedical objects extracted from several heterogeneous datasets from the National Center for Biotechnology Information (NCBI). These objects include but are not limited to scientific papers, keywords, genes, proteins, diseases, and diagnoses. We model hypotheses using Latent Dirichlet Allocation applied on abstracts found near shortest paths discovered within this network, and demonstrate the effectiveness of MOLIERE by performing hypothesis generation on historical data. Our network, implementation, and resulting data are all publicly available for the broad scientific community.


Association of TMEM106B gene polymorphism with age at onset in granulin mutation carriers and plasma granulin protein levels.
To test whether rs1990622 (TMEM106B) is associated with age at onset (AAO) in granulin (GRN) mutation carriers and with plasma GRN levels in mutation carriers and healthy, elderly individuals. Rs1990622 (TMEM106B) was identified as a risk factor for frontotemporal lobar degeneration with TAR DNA-binding protein inclusions (FTLD-TDP) in a recent genome-wide association. Rs1990622 was genotyped in GRN mutation carriers and tested for association with AAO using the Kaplan-Meier method and a Cox proportional hazards model. Alzheimer's Disease Research Center. Subjects We analyzed 50 affected and unaffected GRN mutation carriers from 4 previously reported FTLD-TDP families (HDDD1, FD1, HDDD2, and the Karolinska family). The GRN plasma levels were also measured in 73 healthy, elderly individuals. Age at onset and GRN plasma levels. The risk allele of rs1990622 was associated with a mean decrease of the AAO of 13 years (P = 9.9 × 10(-7)) and with lower plasma GRN levels in both healthy older adults (P = 4 × 10(-4)) and GRN mutation carriers (P = .0027). Analysis of the HapMap database identified a nonsynonymous single-nucleotide polymorphism rs3173615 (T185S) in perfect linkage disequilibrium with rs1990622. The association of rs1990622 with AAO explains, in part, the wide range in the AAO of disease among GRN mutation carriers. We hypothesize that rs1990622 or another variant in linkage disequilibrium could act in a manner similar to APOE in Alzheimer disease, increasing risk for disease in the general population and modifying AAO in mutation carriers. Our results also suggest that genetic variation in TMEM106B may influence risk for FTLD-TDP by modulating secreted levels of GRN.


Efficacy of chloroquine, sulphadoxine-pyrimethamine and amodiaquine for treatment of uncomplicated Plasmodium falciparum malaria in Kajo Keji county, Sudan.
To provide advice on the rational use of antimalarial drugs, Médecins Sans Frontières conducted a randomized, an open label efficacy study in Kajo Keji, an area of high transmission of malaria in southern Sudan. The efficacy of chloroquine (CQ), sulphadoxine-pyrimethamine (SP) and amodiaquine (AQ) were measured in a 28-day in vivo study, with results corrected by PCR genotyping. Of 2010 children screened, 115 children aged 6-59 months with uncomplicated Plasmodium falciparum malaria were randomized into each group to receive a supervised course of treatment. Of these, 114, 103 and 111 were analysed in the CQ, SP and AQ groups, respectively. The overall parasitological failure rates at day 28 were 93.9% [95% confidence interval (CI) 87.3-97.3] for CQ, 69.9% (95% CI 60.0-78.3) for SP, and 25.2% (95% CI 17.7-34.5) for AQ. These results provide important missing data on antimalarial drug efficacy in southern Sudan. They indicate that none of the drugs could be used in monotherapy and suggest that even in combination with artemisinin, cure rates might not be efficacious enough. We recommend a combination of artemether and lumefantrine as first-line treatment for uncomplicated P. falciparum malaria cases in Kajo Keji county.


Viral infections of the lower respiratory tract.
Lower respiratory tract infections (LRTIs) are a global burden to public health and are frequently caused by respiratory viruses. Advances in molecular diagnostic techniques have allowed the identification of previously undetected viral pathogens and have improved our understanding of respiratory virus infections. Here we review the epidemiological and clinical characteristics of recently identified viruses including human metapneumovirus, human coronaviruses NL63 and HKU1, human rhinovirus C, bocavirus, WU and KI polyomaviruses, and parechovirus. The roles of these viruses in LRTIs in children and adults are discussed.


Toxicogenomics in drug discovery and development -- making an impact.
As a branch of pharmacogenomics aimed at predicting drug safety concerns, toxicogenomics drew much excitement with the emergence of technologies such as gene expression microarrays. A few years down the line, the evidence is scant that current approaches to toxicogenomics are really making an impact in areas such as preclinical toxicology. It has been argued that there needs to be a re-focus of application toward high-throughput approaches which combine the best of tissue and genomic modelling. This commentary gives a brief introduction to in vitro toxicogenomics, drawn from the perspectives of the specialist toxicogenomics company, SimuGen.


Abundance distributions imply elevated complexity of post-Paleozoic marine ecosystems.
Likelihood analyses of 1176 fossil assemblages of marine organisms from Phanerozoic (i.e., Cambrian to Recent) assemblages indicate a shift in typical relative-abundance distributions after the Paleozoic. Ecological theory associated with these abundance distributions implies that complex ecosystems are far more common among Meso-Cenozoic assemblages than among the Paleozoic assemblages that preceded them. This transition coincides not with any major change in the way fossils are preserved or collected but with a shift from communities dominated by sessile epifaunal suspension feeders to communities with elevated diversities of mobile and infaunal taxa. This suggests that the end-Permian extinction permanently altered prevailing marine ecosystem structure and precipitated high levels of ecological complexity and alpha diversity in the Meso-Cenozoic.


Progress on incorporating the patient perspective in outcome assessment in rheumatology and the emergence of life impact measures at OMERACT 9.
The Patient Perspective Workshop included over 100 researchers and 18 patient participants from 8 countries. Following preconference reading and short plenary presentations, breakout groups considered work undertaken on measurement of sleep, assessing interventions to develop the effective consumer, and assessing psychological and educational interventions. The workshop explored the best way to identify other outcome domains (and instruments) that should be measured in observational or interventional studies with broader intentions than simply altering outcomes captured in the traditional "core set" plus fatigue. Four sleep questionnaires showed promise and will be the subject of further study. The Effective Consumer scale (EC-17) was reviewed and the concept Effective Consumer was well received. Participants thought it worthwhile to measure the skills and attributes of an effective consumer and develop an intervention that would include education in all of the scale's categories. Assessment of educational and psychological interventions requires a wider set of instruments than is currently used; these should relate to the purpose of the intervention. This principle was extended to include wider measures of the impact of disease on life, as indicated in the International Classification of Functioning, Disability and Health. Life impact measure sets covering domains appropriate to different rheumatic conditions and focused on different interventions might be defined by future OMERACT consensus. Measurement instruments within these domains that are valid for use in rheumatic conditions can then be identified and, in the case of psychological and educational interventions, chosen to fit with the purpose of the intervention.


Decorrelation by recurrent inhibition in heterogeneous neural circuits.
The activity of neurons is correlated, and this correlation affects how the brain processes information. We study the neural circuit mechanisms of correlations by analyzing a network model characterized by strong and heterogeneous interactions: excitatory input drives the fluctuations of neural activity, which are counterbalanced by inhibitory feedback. In particular, excitatory input tends to correlate neurons, while inhibitory feedback reduces correlations. We demonstrate that heterogeneity of synaptic connections is necessary for this inhibition of correlations. We calculate statistical averages over the disordered synaptic interactions and apply our findings to both a simple linear model and a more realistic spiking network model. We find that correlations at zero time lag are positive and of magnitude K(-1/2) where K is the number of connections to a neuron. Correlations at longer timescales are of smaller magnitude, of order K(-1), implying that inhibition of correlations occurs quickly, on a timescale of K(-1/2). The small magnitude of correlations agrees qualitatively with physiological measurements in the cerebral cortex and basal ganglia. The model could be used to study correlations in brain regions dominated by recurrent inhibition, such as the striatum and globus pallidus.


A pediatric correlational study of stride interval dynamics, energy expenditure and activity level.
The strength of time-dependent correlations known as stride interval (SI) dynamics has been proposed as an indicator of neurologically healthy gait. Most recently, it has been hypothesized that these dynamics may be necessary for gait efficiency although the supporting evidence to date is scant. The current study examines over-ground SI dynamics, and their relationship with the cost of walking and physical activity levels in neurologically healthy children aged nine to 15 years. Twenty participants completed a single experimental session consisting of three phases: 10 min resting, 15 min walking and 10 min recovery. The scaling exponent (α) was used to characterize SI dynamics while net energy cost was measured using a portable metabolic cart, and physical activity levels were determined based on a 7-day recall questionnaire. No significant linear relationships were found between a and the net energy cost measures (r < .07; p > .25) or between α and physical activity levels (r = .01, p = .62). However, there was a marked reduction in the variance of α as activity levels increased. Over-ground stride dynamics do not appear to directly reflect energy conservation of gait in neurologically healthy youth. However, the reduction in the variance of α with increasing physical activity suggests a potential exercise-moderated convergence toward a level of stride interval persistence for able-bodied youth reported in the literature. This latter finding warrants further investigation.


Purification and functional characterisation of rhinocerase, a novel serine protease from the venom of Bitis gabonica rhinoceros.
Serine proteases are a major component of viper venoms and are thought to disrupt several distinct elements of the blood coagulation system of envenomed victims. A detailed understanding of the functions of these enzymes is important both for acquiring a fuller understanding of the pathology of envenoming and because these venom proteins have shown potential in treating blood coagulation disorders. In this study a novel, highly abundant serine protease, which we have named rhinocerase, has been isolated and characterised from the venom of Bitis gabonica rhinoceros using liquid phase isoelectric focusing and gel filtration. Like many viper venom serine proteases, this enzyme is glycosylated; the estimated molecular mass of the native enzyme is approximately 36 kDa, which reduces to 31 kDa after deglycosylation. The partial amino acid sequence shows similarity to other viper venom serine proteases, but is clearly distinct from the sequence of the only other sequenced serine protease from Bitis gabonica. Other viper venom serine proteases have been shown to exert distinct biological effects, and our preliminary functional characterization of rhinocerase suggest it to be multifunctional. It is capable of degrading alpha and beta chains of fibrinogen, dissolving plasma clots and of hydrolysing a kallikrein substrate. A novel multifunctional viper venom serine protease has been isolated and characterised. The activities of the enzyme are consistent with the known in vivo effects of Bitis gabonica envenoming, including bleeding disorders, clotting disorders and hypotension. This study will form the basis for future research to understand the mechanisms of serine protease action, and examine the potential for rhinocerase to be used clinically to reduce the risk of human haemostatic disorders such as heart attacks and strokes.