Vacuolar-type H(+)-ATPase subunits and the neurogenic protein big brain are required for optimal copper and zinc uptake.
Copper and zinc homeostasis in polarized epithelial cells requires the correct localization and regulation of membrane-bound transport proteins at the apical and basolateral cell membranes. We have identified a subunit of the vacuolar-type H(+)-ATPase (V-ATPase) complex, vhaPPA1-2, and the Drosophila aquaporin homolog big brain (bib), as being required for the correct localization of the copper uptake transporters Ctr1A and Ctr1B and the zinc uptake protein dZip89B and hence necessary for optimal copper and zinc accumulation in vivo. Knockdown of vhaPPA1-2 or bib resulted in cuticle hypo-pigmentation phenotypes typical of copper deficiency in the fly and induction of midgut Ctr1B expression, a known response to low cellular copper levels. Furthermore, midgut-specific knockdown of bib increased tolerance to elevated dietary zinc levels. Ctr1A, Ctr1B and dZip89B are normally localized to the apical plasma membrane. Upon knockdown of vhaPPA1-2 or bib, this localization was strongly disrupted as was that of the generic plasma membrane marker CD8-GFP, indicating that these two genes are not acting specifically on metal ion homeostasis but rather are necessary for general apical membrane protein localization in polarized epithelial cells. These results suggest that metal ion transport is particularly sensitive to disturbances in cellular protein localization processes.


An evaluation of analytical methods, air sampling techniques, and airborne occupational exposure of metalworking fluids.
This article summarizes an assessment of air sampling and analytical methods for both oil and water-based metalworking fluids (MWFs). Three hundred and seventy-four long-term area and personal airborne samples were collected at four plants using total (closed-face) aerosol samplers and thoracic samplers. A direct-reading device (DustTrak) was also used. The processes sampled include steel tube making, automotive component manufacturing, and small part manufacturing in a machine shop. The American Society for Testing and Materials (ASTM) Method PS42-97 of analysis was evaluated in the laboratory. This evaluation included sample recovery, determination of detection limits, and stability of samples during storage. Results of the laboratory validation showed (a) the sample recovery to be about 87%, (b) the detection limit to be 35 microg, and (c) sample stability during storage at room temperature to decline rapidly within a few days. To minimize sample loss, the samples should be stored in a freezer and analyzed within a week. The ASTM method should be the preferred method for assessing metalworking fluids (MWFs). The ratio of thoracic aerosol to total aerosol ranged from 0.6 to 0.7. A similar relationship was found between the thoracic extractable aerosol and total extractable aerosol. The DustTrak, with 10-microm sampling head, was useful in pinpointing the areas of potential exposure. MWF exposure at the four plants ranged from 0.04 to 3.84 mg/m3 with the geometric mean ranging between 0.22 to 0.59 mg/m3. Based on this data and the assumption of log normality, MWF exposures are expected to exceed the National Institute for Occupational Safety and Health recommended exposure limit of 0.5 mg/m3 as total mass and 0.4 mg/m3 as thoracic mass about 38% of the time. In addition to controlling airborne MWF exposure, full protection of workers would require the institution of programs for fluid management and dermal exposure prevention.


Overexpression of a cytochrome P450 and a UDP-glycosyltransferase is associated with imidacloprid resistance in the Colorado potato beetle, Leptinotarsa decemlineata.
Current control of insect pests relies on chemical insecticides, however, insecticide resistance development by pests is a growing concern in pest management. The main mechanisms for insecticide resistance typically involve elevated activity of detoxifying enzymes and xenobiotic transporters that break-down and excrete insecticide molecules. In this study, we investigated the molecular mechanisms of imidacloprid resistance in the Colorado potato beetle, Leptinotarsa decemlineata (Say) (Coleoptera: Chrysomelidae), an insect pest notorious for its capacity to develop insecticide resistance rapidly. We compared the transcriptome profiles of imidacloprid-resistant and sensitive beetle strains and identified 102 differentially expressed transcripts encoding detoxifying enzymes and xenobiotic transporters. Of these, 74 were up-regulated and 28 were down-regulated in the resistant strain. We then used RNA interference to knock down the transcript levels of seven up-regulated genes in the resistant beetles. Ingestion of double-stranded RNA successfully knocked down the expression of the genes for three cytochrome P450s (CYP6BQ15, CYP4Q3 and CYP4Q7), one ATP binding cassette (ABC) transporter (ABC-G), one esterase (EST1), and two UDP-glycosyltransferases (UGT1 and UGT2). Further, we demonstrated that silencing of CYP4Q3 and UGT2 significantly increased susceptibility of resistant beetles to imidacloprid, indicating that overexpression of these two genes contributes to imidacloprid resistance in this resistant strain.


Hippocampal degeneration differentiates diffuse Lewy body disease (DLBD) from Alzheimer's disease: light and electron microscopic immunocytochemistry of CA2-3 neurites specific to DLBD.
Immunocytochemistry with antibodies to ubiquitin is currently the most sensitive method for detecting cortical Lewy bodies, which are a sine qua non for the diagnosis of diffuse Lewy body disease (DLBD), an increasingly recognized form of primary degenerative dementia. In the systematic application of ubiquitin immunocytochemistry to sections of hippocampus from control subjects and patients with a wide spectrum of neurodegenerative diseases, we noted the frequent occurrence of ubiquitin-immunoreactive neurites in the CA2-3 region in DLBD. The nature of these neurites was investigated with immunocytochemistry in DLBD, Alzheimer's disease (AD), normal elderly subjects, and Parkinson's disease (PD). Although the number of neurites varied from case to case, they were virtually always detected in DLBD but not in normal, AD, or PD brains. Double immunolabeling studies with anti-ubiquitin demonstrated a small fraction of double-stained neurites with antibodies to neurofilament or Alz-50, but no double staining with an antibody to Alzheimer neurofibrillary tangles. These results are different from those for neurites in AD, which are rarely seen in CA2-3 and which are immunoreactive with all these antibodies. Neuritic degeneration in the CA2-3 region of the hippocampus appears to be a specific histopathologic feature of DLBD.


Assessing trends in vaccine efficacy by pathogen genetic distance.
Preventive vaccines are an effective public health intervention for reducing the burden of infectious diseases, but have yet to be developed for several major infectious diseases. Vaccine sieve analysis studies whether and how the efficacy of a vaccine varies with the genetics of the infectious pathogen, which may help guide future vaccine development and deployment. A standard statistical approach to sieve analysis compares the effect of the vaccine to prevent infection and disease caused by pathogen types defined dichotomously as genetically near or far from a reference pathogen strain inside the vaccine construct. For example, near may be defined by amino acid identity at all amino acid positions considered in a multiple alignment and far defined by at least one amino acid difference. An alternative approach is to study the efficacy of the vaccine as a function of genetic distance from a pathogen to a reference vaccine strain where the distance cumulates over the set of amino acid positions. We propose a nonparametric method for estimating and testing the trend in the effect of a vaccine across genetic distance. We illustrate the operating characteristics of the estimator via simulation and apply the method to a recent preventive malaria vaccine efficacy trial.


Two related strains of feline infectious peritonitis virus isolated from immunocompromised cats infected with a feline enteric coronavirus.
Two groups of cats were experimentally infected orally with the cat-passaged RM strain of feline enteric coronavirus (FECV-RM). One group of cats (n = 19) had been chronically infected with feline immunodeficiency virus (FIV) for over 6 years, while a second control group (n = 20) consisted of FIV-naive siblings. Fecal virus shedding of FECV occurred in both groups starting on day 3 postinfection, nearly ceased by 4 weeks in FIV-uninfected cats, but remained at high levels in FIV-infected animals. FIV-infected cats shed virus for a longer period of time and at levels 10 to 100 times greater than those for FIV-uninfected cats. The coronavirus antibody response of the FIV-infected cats was delayed and of reduced titer compared with that of the FIV-uninfected animals. Cats in both groups remained asymptomatic for the first two months following FECV-RM infection; however, 8 to 10 weeks postinfection two cats in the FIV-infected group developed feline infectious peritonitis (FIP). The FIP viruses (designated FIPV-UCD9 and -UCD10) isolated from these two cats had almost complete genetic homology to each other and to the infecting FECV-RM. However, unlike FECV-RM, they readily induced FIP when inoculated intraperitoneally into specific-pathogen-free cats. This study confirms that FIPVs are frequently and rapidly arising mutants of FECV. Immunosuppression caused by chronic FIV infection may have enhanced the creation and selection of FIPV mutants by increasing the rate of FECV replication in the bowel and inhibiting the host's ability to combat the mutant viruses once they occurred.


Effect of simulator training on driving after stroke: a randomized controlled trial.
Neurologically impaired persons seem to benefit from driving-training programs, but there is no convincing evidence to support this notion. The authors therefore investigated the effect of simulator-based training on driving after stroke. Eighty-three first-ever subacute stroke patients entered a 5-week 15-hour training program in which they were randomly allocated to either an experimental (simulator-based training) or control (driving-related cognitive tasks) group. Performance in off-road evaluations and an on-road test were used to assess the driving ability of subjects pre- and post-training. Outcome of an official predriving assessment administered 6 to 9 months poststroke was also considered. Both groups significantly improved in a visual and many neuropsychological evaluations and in the on-road test after training. There were no significant differences between both groups in improvements from pre- to post-training except in the "road sign recognition test" in which the experimental subjects improved more. Significant improvements in the three-class decision ("fit to drive," "temporarily unfit to drive," and "unfit to drive") were found in favor of the experimental group post-training. Academic qualification and overall disability together determined subjects that benefited most from the simulator-based driving training. Significantly more experimental subjects (73%) than control subjects (42%) passed the follow-up official predriving assessment and were legally allowed to resume driving. Simulator-based driving training improved driving ability, especially for well educated and less disabled stroke patients. However, the findings of the study may have been modified as a result of the large number of dropouts and the possibility of some neurologic recovery unrelated to training.


A developmental toxicity assay of Carpesii Fructus on zebrafish embryos/larvae.
Carpesii Fructus, the dried fruit of Carpesium abrotanoides L., has been used as a traditional Chinese medicine for centuries to kill intestinal parasites in children. It has been recorded as a mildly toxic medicine in the Chinese pharmacopoeia. However, little proof of its toxicology has been reported in modern pharmacology. This study investigated for the first time its developmental toxicity on zebrafish embryos/larvae from 6 to 96 h post-fertilization (hpf). In addition, the enzymes and genes associated with oxidative stress and apoptosis were tested to investigate the potential toxicologic mechanism preliminarily. The observation of toxicologic endpoints showed the developmental toxicity of Carpesii Fructus. Pericardial edema, yolk sac edema, bleeding tendency, and enlarged yolk were the most commonly occurring morphological changes observed in our study. According to the results of acridine orange staining and morphological observation, the developing heart was speculated to be the target organ of toxicity. Furthermore, Carpesii Fructus exposure changed the activities of defense enzymes, increased malondialdehyde (MDA) content, decreased caspase-3 activity, and altered mRNA levels of related genes (ogg1, p53, Cu/Zn-Sod, Mn-Sod, and Cat↓; Gpx↑) in zebrafish larvae, indicating that oxidative stress and additional apoptosis should have roles in the developmental toxicity of Carpesii Fructus. This is the first study that provides proof of modern pharmacology on the teratogenicity and possible toxicologic mechanism of Carpesii Fructus.


Contrasting parents' and pediatricians' perspectives on shared decision-making in ADHD.
The goal was to compare how parents and clinicians understand shared decision-making (SDM) in attention-deficit/hyperactivity disorder (ADHD), a prototype for SDM in pediatrics. We conducted semi-structured interviews with 60 parents of children 6 to 12 years of age with ADHD (50% black and 43% college educated) and 30 primary care clinicians with varying experience. Open-ended interviews explored how pediatric clinicians and parents understood SDM in ADHD. Interviews were taped, transcribed, and then coded. Data were analyzed by using a modified grounded theory approach. Parents and clinicians both viewed SDM favorably. However, parents described SDM as a partnership between equals, with physicians providing medical expertise and the family contributing in-depth knowledge of the child. In contrast, clinicians understood SDM as a means to encourage families to accept clinicians' preferred treatment. These findings affected care because parents mistrusted clinicians whose presentation they perceived as biased. Both groups discussed how real-world barriers limit the consideration of evidence-based options, and they emphasized the importance of engaging professionals, family members, and/or friends in SDM. Although primary themes did not differ according to race, white parents more commonly received support from medical professionals in their social networks. Despite national guidelines prioritizing SDM in ADHD, challenges to implementing the process persist. Results suggest that, to support SDM in ADHD, modifications are needed at the practice and policy levels, including clinician training, incorporation of decision aids and improved strategies to facilitate communication, and efforts to ensure that evidence-based treatment is accessible.


On Efficient Deployment of Wireless Sensors for Coverage and Connectivity in Constrained 3D Space.
Sensor networks have been used in a rapidly increasing number of applications in many fields. This work generalizes a sensor deployment problem to place a minimum set of wireless sensors at candidate locations in constrained 3D space to k-cover a given set of target objects. By exhausting the combinations of discreteness/continuousness constraints on either sensor locations or target objects, we formulate four classes of sensor deployment problems in 3D space: deploy sensors at Discrete/Continuous Locations (D/CL) to cover Discrete/Continuous Targets (D/CT). We begin with the design of an approximate algorithm for DLDT and then reduce DLCT, CLDT, and CLCT to DLDT by discretizing continuous sensor locations or target objects into a set of divisions without sacrificing sensing precision. Furthermore, we consider a connected version of each problem where the deployed sensors must form a connected network, and design an approximation algorithm to minimize the number of deployed sensors with connectivity guarantee. For performance comparison, we design and implement an optimal solution and a genetic algorithm (GA)-based approach. Extensive simulation results show that the proposed deployment algorithms consistently outperform the GA-based heuristic and achieve a close-to-optimal performance in small-scale problem instances and a significantly superior overall performance than the theoretical upper bound.


The Clavien-Dindo classification of surgical complications: five-year experience.
The lack of consensus on how to define and grade adverse postoperative events has greatly hampered the evaluation of surgical procedures. A new classification of complications, initiated in 1992, was updated 5 years ago. It is based on the type of therapy needed to correct the complication. The principle of the classification was to be simple, reproducible, flexible, and applicable irrespective of the cultural background. The aim of the current study was to critically evaluate this classification from the perspective of its use in the literature, by assessing interobserver variability in grading complex complication scenarios and to correlate the classification grades with patients', nurses', and doctors' perception. Reports from the literature using the classification system were systematically analyzed. Next, 11 scenarios illustrating difficult cases were prepared to develop a consensus on how to rank the various complications. Third, 7 centers from different continents, having routinely used the classification, independently assessed the 11 scenarios. An agreement analysis was performed to test the accuracy and reliability of the classification. Finally, the perception of the severity was tested in patients, nurses, and physicians by presenting 30 scenarios, each illustrating a specific grade of complication. We noted a dramatic increase in the use of the classification in many fields of surgery. About half of the studies used the contracted form, whereas the rest used the full range of grading. Two-thirds of the publications avoided subjective terms such as minor or major complications. The study of 11 difficult cases among various centers revealed a high degree of agreement in identifying and ranking complications (89% agreement), and enabled a better definition of unclear situations. Each grade of complications significantly correlated with the perception by patients, nurses, and physicians (P < 0.05, Kruskal-Wallis test). This 5-year evaluation provides strong evidence that the classification is valid and applicable worldwide in many fields of surgery. No modification in the general principle of classification is warranted in view of the use in ongoing publications and trials. Subjective, inaccurate, or confusing terms such as "minor or major" should be removed from the surgical literature.


The probabilistic niche model reveals the niche structure and role of body size in a complex food web.
The niche model has been widely used to model the structure of complex food webs, and yet the ecological meaning of the single niche dimension has not been explored. In the niche model, each species has three traits, niche position, diet position and feeding range. Here, a new probabilistic niche model, which allows the maximum likelihood set of trait values to be estimated for each species, is applied to the food web of the Benguela fishery. We also developed the allometric niche model, in which body size is used as the niche dimension. About 80% of the links in the empirical data are predicted by the probabilistic niche model, a significant improvement over recent models. As in the niche model, species are uniformly distributed on the niche axis. Feeding ranges are exponentially distributed, but diet positions are not uniformly distributed below the predator. Species traits are strongly correlated with body size, but the allometric niche model performs significantly worse than the probabilistic niche model. The best-fit parameter set provides a significantly better model of the structure of the Benguela food web than was previously available. The methodology allows the identification of a number of taxa that stand out as outliers either in the model's poor performance at predicting their predators or prey or in their parameter values. While important, body size alone does not explain the structure of the one-dimensional niche.


[Assessment of job strain and its consequencies in a large public organisation. Findings from the SEMM Study].
The demand-control model originally developed by Robert Karasek is in Italy the preferred tool to investigate perceived work stress due to work-related organizational constrains. We wish to report the comprehensive results of the SEMM Study, carried on a wide sample of civil servants. N. 5271 women and 2601 men, employed at the Municipality of Milan in the years 1991-1996 were enrolled into the study. The overall participation rate was high in both gender group (75% or more), indicating a good compliance of employees for health prevention programmes carried out in work settings. Each participant, who has given consent, in addition to the medical examinations and biological tests related to the investigation of work exposures, underwent to a structured procedure to measure cardiovascular risk factors, according to the methods developed in the WHO MONICA Project, job strain adopting the Job Content Questionnaire (JCQ), and the Baecke Questionnaire to investigate major quotes of physical activity. In this contest the JCQ has shown an acceptable level of internal and external consistency as well as of acceptance, measured by employees compliance. Psychological job demand and decision latitude can be assessed with two different JCQ revisions available in Italian, which were validated with the contribution of the author, at different complexity, but with comparable results of weighted scores. For a comprehensive assessment of the working conditions social support at work is also of relevance. In the work public sector considered, the JCQ major scores resulted to be valid descriptors of key aspects of the work organization. The concurrent assessment of sick leaves, known marker of burnout, allows to identify work- and individual-related determinants and, in a specific work setting, to give indications for coping actions which may improve workers' integration. In addition, the assessment of cardiovascular risk factors, carried out with standardised and then reliable methods, allow to measure overall global CVD risk and to identify unhealthy behaviours that can be addressed with specific preventive programmes.


Wnts Are Expressed in the Ependymal Region of the Adult Spinal Cord.
The Wnt family of proteins plays key roles during central nervous system development and in several physiological processes during adulthood. Recently, experimental evidence has linked Wnt-related genes to regulation and maintenance of stem cells in the adult neurogenic niches. In the spinal cord, the ependymal cells surrounding the central canal form one of those niches, but little is known about their Wnt expression patterns. Using microdissection followed by TaqMan® low-density arrays, we show here that the ependymal regions of young, mature rats and adult humans express several Wnt-related genes, including ligands, conventional and non-conventional receptors, co-receptors, and soluble inhibitors. We found 13 genes shared between rats and humans, 4 exclusively expressed in rats and 9 expressed only in humans. Also, we observed a reduction with age on spontaneous proliferation of ependymal cells in rats paralleled by a decrease in the expression of Fzd1, Fzd8, and Fzd9. Our results suggest a role for Wnts in the regulation of the adult spinal cord neurogenic niche and provide new data on the specific differences in this region between humans and rodents.


Estimating the Societal Benefits of THA After Accounting for Work Status and Productivity: A Markov Model Approach.
Demand for total hip arthroplasty (THA) is high and expected to continue to grow during the next decade. Although much of this growth includes working-aged patients, cost-effectiveness studies on THA have not fully incorporated the productivity effects from surgery. We asked: (1) What is the expected effect of THA on patients' employment and earnings? (2) How does accounting for these effects influence the cost-effectiveness of THA relative to nonsurgical treatment? Taking a societal perspective, we used a Markov model to assess the overall cost-effectiveness of THA compared with nonsurgical treatment. We estimated direct medical costs using Medicare claims data and indirect costs (employment status and worker earnings) using regression models and nonparametric simulations. For direct costs, we estimated average spending 1 year before and after surgery. Spending estimates included physician and related services, hospital inpatient and outpatient care, and postacute care. For indirect costs, we estimated the relationship between functional status and productivity, using data from the National Health Interview Survey and regression analysis. Using regression coefficients and patient survey data, we ran a nonparametric simulation to estimate productivity (probability of working multiplied by earnings if working minus the value of missed work days) before and after THA. We used the Australian Orthopaedic Association National Joint Replacement Registry to obtain revision rates because it contained osteoarthritis-specific THA revision rates by age and gender, which were unavailable in other registry reports. Other model assumptions were extracted from a previously published cost-effectiveness analysis that included a comprehensive literature review. We incorporated all parameter estimates into Markov models to assess THA effects on quality-adjusted life years and lifetime costs. We conducted threshold and sensitivity analyses on direct costs, indirect costs, and revision rates to assess the robustness of our Markov model results. Compared with nonsurgical treatments, THA increased average annual productivity of patients by USD 9503 (95% CI, USD 1446-USD 17,812). We found that THA increases average lifetime direct costs by USD 30,365, which were offset by USD 63,314 in lifetime savings from increased productivity. With net societal savings of USD 32,948 per patient, total lifetime societal savings were estimated at almost USD 10 billion from more than 300,000 THAs performed in the United States each year. Using a Markov model approach, we show that THA produces societal benefits that can offset the costs of THA. When comparing THA with other nonsurgical treatments, policymakers should consider the long-term benefits associated with increased productivity from surgery. Level III, economic and decision analysis.


Olestra consumption does not predict serum concentrations of carotenoids and fat-soluble vitamins in free-living humans: early results from the sentinel site of the olestra post-marketing surveillance study.
In 1996, the U.S. Food and Drug Administration approved olestra, a fat substitute, for use in snack foods. Previous studies had shown that olestra consumption could reduce absorption of carotenoids and fat-soluble vitamins. To determine the association between consumption of olestra-containing snack foods and serum concentrations of carotenoids and fat-soluble vitamins in a free-living population, we interviewed independent population-based cross-sectional samples of 1043 adults before olestra was available and 933 adults 9 mo after olestra snacks were introduced into the marketplace in Marion County, IN, the first major test market for olestra. A cohort composed of 403 adults from the first survey, oversampling those most frequently reporting olestra consumption during follow-up telephone interviews, completed a second survey. We assessed diet, lifestyle factors and olestra consumption, and collected blood for assays for the serum concentrations of six carotenoids, four fat-soluble vitamins and lipids. Nine months after the introduction of olestra into the marketplace, 15.5% of Marion County residents reported consuming an olestra-containing snack in the previous month, with a median frequency among consumers of 3.0 times per month. There were no significant associations or consistent trends for decreased serum carotenoids or fat-soluble vitamins associated with olestra consumption, although cohort members consuming >/=2 g/d of olestra had adjusted total serum carotenoids 15% lower compared with baseline. There were increases in serum vitamin K concentrations associated with olestra consumption (P = 0.03 in the cross section and P = 0.06 in the cohort). In summary, there was no statistically significant evidence in this free-living population of associations between olestra consumption and decreased serum concentrations of carotenoids and fat-soluble vitamins.


Abnormalities in α/β-CaMKII and related mechanisms suggest synaptic dysfunction in hippocampus of LPA1 receptor knockout mice.
Lysophosphatidic acid (LPA) is a natural lysophospholipid that regulates neuronal maturation. In mice, the deletion of the LPA1 receptor causes some phenotypic defects partly overlapping with those found in schizophrenia. In this study, we identified molecular abnormalities in hippocampal synaptic mechanisms involved in glutamatergic neurotransmission, which allow further characterization of synaptic aberrations in LPA1 knockout (KO) mice. At the synaptic level, we found dysregulation of Ca2+/calmodulin (CaM)-dependent kinase II (CaMKII) activity and phosphorylation, with markedly higher Ca2+-dependent kinase activity, probably related to increased expression levels of the β isoform of CaMKII. Conversely, although the synaptic Ca2+-independent activity of the enzyme was unchanged, autophosphorylation levels of both α and β isoforms were significantly increased in LPA1 KO mice. Moreover, in LPA1 KO mice the α/β isoform ratio of CaMKII, which plays a key role in neuronal maturation during development, was markedly decreased, as found previously in schizophrenia patients. At post-synaptic level, LPA1 KO mice showed changes in expression, phosphorylation and interactions of NMDA and AMPA receptor subunits that are consistent with basal strengthening of glutamatergic synapses. However, we measured a reduction of nuclear cAMP responsive element-binding protein phosphorylation, suggesting that activation of the NMDA receptor does not occur at the intracellular signalling level. At the presynaptic level, in line with previous evidence from schizophrenia patients and animal models of pathology, LPA1 KO mice showed accumulation of SNARE protein complexes. This study shows that CaMKII and related synaptic mechanisms at glutamatergic synapses are strongly dysregulated in LPA1 KO mice.


Progress towards a dengue vaccine.
The spread of dengue virus throughout the tropics represents a major, rapidly growing public health problem with an estimated 2.5 billion people at risk of dengue fever and the life-threatening disease, severe dengue. A safe and effective vaccine for dengue is urgently needed. The pathogenesis of severe dengue results from a complex interaction between the virus, the host, and, at least in part, immune-mediated mechanisms. Vaccine development has been slowed by fears that immunisation might predispose individuals to the severe form of dengue infection. A pipeline of candidate vaccines now exists, including live attenuated, inactivated, chimeric, DNA, and viral-vector vaccines, some of which are at the stage of clinical testing. In this Review, we present what is understood about dengue pathogenesis and its implications for vaccine design, the progress that is being made in the development of a vaccine, and the future challenges.


Application of the essential oil from copaiba (Copaifera langsdori Desf.) for acne vulgaris: a double-blind, placebo-controlled clinical trial.
Copaiba oil-resin is widely used in traditional medicine due to its anti-inflammatory, healing, and antiseptic activities. This research aims to extract and evaluate the qualitative and quantitative composition of copaiba essential oil from the oil-resin, and test its effects, after incorporation in a gel applied in volunteers with acne, in a double-blind placebo controlled clinical trial. The essential oil was extracted by steam distillation, and purified by freezing to remove the residual remnant water. The density of the essential oil was gravimetrically determined by weighing 1 mL of liquid at 20 degree C. The identification of the essential oil components was carried out through high-resolution gas chromatography analysis, coupled with mass spectrometry. The essential oil has a density of 0.9175 mg/mL and was composed of 48 substances, 14 of which were the major components representing 95.80% of total essential oil composition. Cis-thujopsene was the main component (46.96% of total essential oil composition). The surface affected with acne decreased when treated with placebo (F = 13.931, p = 0.001, r = 0.518; r2 = 0.268), but the linear model could explain only 26.8% of total variance in original data matrix. There was a highly significant decrease in the surface affected with acne in the areas treated with the 1.0% copaiba essential oil preparation (F = 86.494, p = 0.000, r = 0.834; r2 = 0.695).


[Breastfeeding and maternal medications].
To contribute with information about the adequate administration of drugs during breastfeeding. MEDLINE articles from 1993 to 2004, and Lilacs articles from 1995 to 2004 were selected in Portuguese, Spanish and English, by including the following keywords: breastfeeding, lactation, drugs and medicines. Other updated references found in articles and books were also included in this review, in order to provide additional information. Most of the drugs are compatible with breastfeeding. Few were considered inadequate, such as antineoplastic drugs, radiopharmaceuticals and drugs of abuse. Some drugs require concern, as they may cause adverse effects in breastfed babies or reduce the mother's breast milk volume. However, further knowledge on some medicines during lactation is required. The fundamental principle in the prescription of medicines for lactating mothers is mostly based on the concept of risk and benefit. The option must be, as much as possible, for a drug that has already been studied, which is little released in the maternal milk or that does not mean an apparent risk for the infant's health. Medicines that reduce the mother's production of milk should be avoided during the lactation period. The use of galactogogos is reserved for particular situations. Therefore, only safety drugs should be administered during breastfeeding, which should rarely be discouraged or discontinued in such cases.


Patients' experiences and views of cascade screening for familial hypercholesterolemia (FH): a qualitative study.
Familial DNA cascade screening for familial hypercholesterolemia (FH) has recently been introduced in Scotland. This study investigated index patients' experiences of DNA testing and mediating cascade screening. Thirty-eight patients with a clinical diagnosis of definite or possible FH who had undergone DNA testing in the lipid clinic took part in semi-structured qualitative interviews. All patients were positive about DNA screening being undertaken by familiar and trusted clinicians within the lipid clinic. Most patients had already cascaded close relatives for serum cholesterol testing following their attendance at the lipid clinic. Identified mutation carriers who had attended the genetics clinic (n = 15) for a cascading appointment described finding this consultation helpful because it identified other at-risk family members and provided them with tailored information for their relatives. Participants who expressed a preference said they favoured indirect (patient-mediated) methods of cascading as they considered indirect approaches to be less threatening to family members than direct clinical contact. We conclude that DNA screening and indirect familial cascading is perceived as highly acceptable to index patients with FH. However, while indirect cascading methods may be more acceptable to patients, they do not yield the same numbers as more direct methods. There is, therefore, a need for further systematic research to investigate patients', family members' and staff views of the acceptability of direct versus indirect methods of cascade screening.


Ethanol-inducible cytochrome P450 in rabbits metabolizes enflurane.
Following anaesthesia with enflurane, some patients receiving isoniazid have increased serum concentrations of fluoride ion, presumably because of induction of an isozyme of cytochrome P450 which is responsible for enflurane biodegradation. In rats, isoniazid and ethanol enhance metabolism of enflurane and also induce a form of cytochrome P450 which is homologous with a form of rabbit liver cytochrome P450 known as 3a. Isoniazid, ethanol and imidazole increase the concentration of cytochrome P450 3a in hepatic microsomes. We have pretreated rabbits with imidazole, the most potent of the three inducers of isozyme 3a, to determine if the hepatic microsomal metabolism of enflurane is enhanced and if purified isozyme 3a catalyses the oxidation of enflurane. Imidazole produced a 250% increase in the hepatic microsomal metabolism of enflurane, sevoflurane, methoxyflurane and the control substrate, aniline. Polyclonal antibodies to cytochrome P450 3a inhibited 90% of enflurane metabolism, but only 40% of methoxyflurane biotransformation in the microsomes from imidazole-pretreated rabbits. Thus isozyme 3a or a structurally similar cytochrome P450 seemed to catalyse almost all microsomal metabolism of enflurane. In addition, purified cytochrome P450 3a catalysed the metabolism of enflurane, sevoflurane and methoxyflurane, and the oxidation of these anaesthetics by cytochrome P450 3a was stimulated four-fold by cytochrome b5, a protein which serves as an alternate source of electrons for some cytochrome P450 reactions.


Simulation of scanning laser techniques for optical imaging of blood-related intrinsic signals.
Optical imaging of intrinsic signals detects neural activation patterns by taking video images of the local activity-related changes in the light intensity reflected from neural tissue (intrinsic signals). At red light (605 nm), these signals are caused mainly by local variations of the tissue absorption following deoxygenation of blood. We characterize the image generation process during optical imaging by Monte Carlo simulations of light propagation through a homogeneous model tissue equipped with a local absorber. Conventional video imaging and scanning laser imaging are compared. We find that, compared with video imaging, scanning laser techniques drastically increase both the contrast and the lateral resolution of optical recordings. Also, the maximum depth up to which the signals can be detected is increased by roughly a factor of 2 when scanning laser optical imaging is used. Further, the radial profile of the diffuse-reflectance pattern for each pixel is subject to changes that correlate with the depth of the absorber within the tissue. We suggest a detection geometry for the online measurement of these radial profiles that can be realized by modifying a standard scanning laser ophthalmoscope.


The role of zinc in liver cirrhosis.
Zinc is an essential trace element playing fundamental roles in cellular metabolism. It acts mostly by binding a wide range of proteins, thus affecting a broad spectrum of biological processes, which include cell division, growth and differentiation. Zinc is critical to a large number of structural proteins, enzymatic processes, and transcription factors. Zinc deficiency can result in a spectrum of clinical manifestations, such as poor of appetite, loss of body hair, altered taste and smell, testicular atrophy, cerebral and immune dysfunction, and diminished drug elimination capacity. These are common symptoms in patients with chronic liver diseases, especially liver cirrhosis. The liver is the main organ responsible for the zinc metabolism which can be affected by liver diseases. On the other hand, zinc deficiency may alter hepatocyte functions and also immune responses in inflammatory liver diseases. Liver cirrhosis represents the most advanced stage of chronic liver diseases and is the common outcome of chronic liver injury. It is associated with energy malnutrition, with numerous metabolic disorders, such as hypoalbuminemia, with imbalance between branched-chain amino acids and aromatic amino acids, and with reduced zinc serum concentrations. All these processes can influence the clinical outcome of patients, such ascites, hepatic encephalopathy and hepatocellular carcinoma. In the present review, we summarize the emerging evidence on the pitoval role of zinc in the pathogenesis of liver cirrhosis.


Differences in Determinants: Racialized Obstetric Care and Increases in U.S. State Labor Induction Rates.
Induction of labor (IOL) rates in the United States have nearly tripled since 1990. We examine official U.S. birth records to document increases in states' IOL rates among pregnancies to Black, Latina, and White women. We test if the increases are associated with changes in demographic characteristics and risk factors among states' racial-ethnic childbearing populations. Among pregnancies to White women, increases in state IOL rates are strongly associated with changes in risk factors among White childbearing populations. However, the rising IOL rates among pregnancies to Black and Latina women are not due to changing factors in their own populations but are instead driven by changing factors among states' White childbearing populations. The results suggest systemic racism may be shaping U.S. obstetric care whereby care is not "centered at the margins" but is instead responsive to characteristics in states' White populations.


Application of short-term inhalation studies to assess the inhalation toxicity of nanomaterials.
A standard short-term inhalation study (STIS) was applied for hazard assessment of 13 metal oxide nanomaterials and micron-scale zinc oxide. Rats were exposed to test material aerosols (ranging from 0.5 to 50 mg/m3) for five consecutive days with 14- or 21-day post-exposure observation. Bronchoalveolar lavage fluid (BALF) and histopathological sections of the entire respiratory tract were examined. Pulmonary deposition and clearance and test material translocation into extra-pulmonary organs were assessed. Inhaled nanomaterials were found in the lung, in alveolar macrophages, and in the draining lymph nodes. Polyacrylate-coated silica was also found in the spleen, and both zinc oxides elicited olfactory epithelium necrosis. None of the other nanomaterials was recorded in extra-pulmonary organs. Eight nanomaterials did not elicit pulmonary effects, and their no observed adverse effect concentrations (NOAECs) were at least 10 mg/m3. Five materials (coated nano-TiO2, both ZnO, both CeO2) evoked concentration-dependent transient pulmonary inflammation. Most effects were at least partially reversible during the post-exposure period.Based on the NOAECs that were derived from quantitative parameters, with BALF polymorphonuclear (PMN) neutrophil counts and total protein concentration being most sensitive, or from the severity of histopathological findings, the materials were ranked by increasing toxic potency into 3 grades: lower toxic potency: BaSO4; SiO2.acrylate (by local NOAEC); SiO2.PEG; SiO2.phosphate; SiO2.amino; nano-ZrO2; ZrO2.TODA; ZrO2.acrylate; medium toxic potency: SiO2.naked; higher toxic potency: coated nano-TiO2; nano-CeO2; Al-doped nano-CeO2; micron-scale ZnO; coated nano-ZnO (and SiO2.acrylate by systemic no observed effect concentration (NOEC)). The STIS revealed the type of effects of 13 nanomaterials, and micron-scale ZnO, information on their toxic potency, and the location and reversibility of effects. Assessment of lung burden and material translocation provided preliminary biokinetic information. Based upon the study results, the STIS protocol was re-assessed and preliminary suggestions regarding the grouping of nanomaterials for safety assessment were spelled out.


Early indicators of enduring symptoms in high school athletes with multiple previous concussions.
Despite recent findings of cognitive, emotional, physical, and behavioral symptomatology in retired professional athletes with a history of multiple concussions, there is little systematic research examining these symptoms in high school athletes with a history of concussion. To identify cognitive, emotional, and physical symptoms at baseline in nonconcussed high school athletes based on concussion history. A multicenter sample of 616 high school athletes who completed baseline evaluations were assigned to groups based on history of concussion (none, 1, 2, or more previous concussions). The Post-Concussion Symptom Scale was administered as part of a computerized neuropsychological test battery during athletes' preseason baseline evaluations. Cross-sectional analyses were used to examine symptoms reported at the time of baseline neuropsychological testing. High school athletes with a history of 2 or more concussions showed significantly higher ratings of concussion-related symptoms (cognitive, physical, sleep difficulties) than athletes with a history of one or no previous concussions. It appears that youth athletes who sustain multiple concussions experience a variety of subtle effects, which may be possible precursors of the future onset of concussion-related difficulties.


MyD88 signaling in nonhematopoietic cells protects mice against induced colitis by regulating specific EGF receptor ligands.
Toll-like receptors (TLRs) trigger intestinal inflammation when the epithelial barrier is breached by physical trauma or pathogenic microbes. Although it has been shown that TLR-mediated signals are ultimately protective in models of acute intestinal inflammation [such as dextran sulfate sodium (DSS)-induced colitis], it is less clear which cells mediate protection. Here we demonstrate that TLR signaling in the nonhematopoietic compartment confers protection in acute DSS-induced colitis. Epithelial cells of MyD88/Trif-deficient mice express diminished levels of the epidermal growth factor receptor (EGFR) ligands amphiregulin (AREG) and epiregulin (EREG), and systemic lipopolysaccharide administration induces their expression in the colon. N-ethyl-N-nitrosourea (ENU)-induced mutations in Adam17 (which is required for AREG and EREG processing) and in Egfr both produce a strong DSS colitis phenotype, and the Adam17 mutation exerts its deleterious effect in the nonhematopoietic compartment. The effect of abrogation of TLR signaling is mitigated by systemic administration of AREG. A TLR→MyD88→AREG/EREG→EGFR signaling pathway is represented in nonhematopoietic cells of the intestinal tract, responds to microbial stimuli once barriers are breached, and mediates protection against DSS-induced colitis.


Renal abscess in children.
Three cases of renal abscesses in children are described to illustrate the variable presenting features. An additional 23 pediatric cases, reported over the past ten years, were reviewed for clinical features and therapy. Fever, loin pain, and leukocytosis were common presenting features, but less than half of all abscesses were associated with either an abnormal urinalysis or a positive urine culture. The presenting features were sometimes confused with appendicitis, peritonitis, or a Wilms tumor. An organism was identified in 17 cases--Escherichia coli in 9 children and Staphylococcus aureus in 8 children. The majority of E. coli infections occurred in girls and the majority of S. aureus infections occurred in boys. Reflux was documented in 5 patients, and 2 children had a possible extrarenal source of infection. Antibiotics alone produced a cure in 10 children (38%), but 16 children (62%) required a surgical procedure.


Surfactant-assisted route to synthesize well-aligned ZnO nanorod arrays on sol-gel-derived ZnO thin films.
Anisotropic growth of ZnO nanorod arrays on ZnO thin films was achieved at a temperature of 90 degrees C by a surfactant-assisted soft chemical approach with control over size and orientation. ZnO thin films with c-axis preferred orientation had been achieved by the sol-gel technique. Lengths, diameters, and the degree of alignment of the ZnO nanorods were controlled by changing the experimental parameters. It was observed that the surfactant was essential to restrict the lateral growth of the nanorods, whereas the pH level of the reaction medium controlled the length of the nanorods. On the other hand, the orientation of the nanorods depended on the crystalline orientation of the film as well as the pH of the reaction medium. Room-temperature photoluminescence studies revealed that the ZnO nanorods with the best alignment exhibited the best emission property. The ZnO nanorods exhibited a strong UV emission peak at approximately 3.22 eV, ascribed to the band-edge emission. The field emission studies of the well-aligned nanorod arrays exhibited a low turn-on field of 1.7 V/microm to get an emission current density of 0.1 microA/cm(2).


Identification and Structural Characterization of Naturally-Occurring Broad-Spectrum Cyclic Antibiotics Isolated from Paenibacillus.
The rise of antimicrobial resistance necessitates the discovery and/or production of novel antibiotics. Isolated strains of Paenibacillus alvei were previously shown to exhibit antimicrobial activity against a number of pathogens, such as E. coli, Salmonella, and methicillin-resistant Staphylococcus aureus (MRSA). The responsible antimicrobial compounds were isolated from these Paenibacillus strains and a combination of low and high resolution mass spectrometry with multiple-stage tandem mass spectrometry was used for identification. A group of closely related cyclic lipopeptides was identified, differing primarily by fatty acid chain length and one of two possible amino acid substitutions. Variation in the fatty acid length resulted in mass differences of 14 Da and yielded groups of related MS(n) spectra. Despite the inherent complexity of MS/MS spectra of cyclic compounds, straightforward analysis of these spectra was accomplished by determining differences in complementary product ion series between compounds that differ in molecular weight by 14 Da. The primary peptide sequence assignment was confirmed through genome mining; the combination of these analytical tools represents a workflow that can be used for the identification of complex antibiotics. The compounds also share amino acid sequence similarity to a previously identified broad-spectrum antibiotic isolated from Paenibacillus. The presence of such a wide distribution of related compounds produced by the same organism represents a novel class of broad-spectrum antibiotic compounds.


Heterolytic activation of dihydrogen by platinum and palladium complexes.
Wide bite angle diphosphine ligands were used to prepare [(diphosphine)M(2-(diphenylphosphino)pyridine)](2+) complexes (M = Pd, Pt). Except for the ligand with the largest bite angle, 2-(diphenylphosphino)pyridine coordinates in a bidentate mode leading to bis-chelate complexes. In the case of Xantphos (9,9-dimethyl-4,5-bis(diphenylphosphino)-xanthene, βn = 111°) two types of complexes are formed, in which 2-(diphenylphosphino)pyridine coordinates in a mono- or bidentate fashion, respectively. The crystal structures of three of the Pt complexes were determined. The X-ray crystal structure of [(Xantphos)-Pt(2-(diphenylphosphino)pyridine)](2+) shows that Xantphos coordinates in a tridentate P,O,P fashion. Under dihydrogen pressure, the pyridyl moiety in the platinum complexes can de-coordinate to provide a vacant coordination site at the metal center. Furthermore it can act as an internal base to assist the heterolytic cleavage of dihydrogen. The reaction yields a platinum hydride with a protonated pyridine moiety in close proximity to one another. The structure as well as the reactivity of the complexes towards dihydrogen is governed by the steric requirements of the diphosphines. The crystal structure of [(dppf)PtH(2-(diphenylphosphino)pyridinium)](OTf)2 has been determined. Palladium complexes containing DPEphos or Xantphos decompose under dihydrogen pressure. In the case of dppf slow heterolytic splitting of dihydrogen occurs to form the hydride complex [(dppf)PdH(2-(diphenylphosphino)pyridinium)](OTf)2 which contains a protonated 2-(diphenylphosphino)pyridine ligand. In solution, this compound slowly undergoes P-C bond cleavage of the 2-(diphenylphosphino)pyridine ligand to form [(dppf)Pd(PHPh2)(η(1)-C5H4NH)](OTf)2. When the 6-methyl-2-pyridyldiphenylphosphine ligand is used, the reaction of the palladium complex with dihydrogen is very fast and the hydride complex immediately rearranges to the diphenylphosphino compound resulting from P-C bond cleavage.


Schizophrenia: moving beyond monoamine antagonists.
Schizophrenia is a disabling psychiatric disorder characterized by positive, negative, and cognitive symptoms. The first pharmacological treatments for schizophrenia were discovered by serendipitous, albeit carefully documented, clinical observations. The discovery of chlorpromazine and other dopamine D2 receptor antagonists as antipsychotic agents set the early course of drug discovery in the context of schizophrenia and other psychiatric disorders, and various monoamine receptors became the prime focus of neuropharmacological studies. Success in treating the positive symptoms nevertheless remained limited by the general lack of efficacy in addressing negative symptoms and cognitive impairment. In recent years, several new experimental approaches have emerged for the identification and treatment of different symptom clusters that do not rely on blockade of monoamine receptors. Muscarinic, nicotinic, and glutamatergic signaling mechanisms have become essential to neuropharmacological and behavioral models of discrete aspects of schizophrenia. And as a consequence of these insights, novel drug entities have become available to study and potentially treat the disabling cognitive and negative symptoms of psychiatric disease. Current attempts to target a new range of receptors entail unprecedented fine-tuning in the pharmacological manipulation of specific receptor subtypes.


Value of adding single-nucleotide polymorphism genotypes to a breast cancer risk model.
Adding genotypes from seven single-nucleotide polymorphisms (SNPs), which had previously been associated with breast cancer, to the National Cancer Institute's Breast Cancer Risk Assessment Tool (BCRAT) increases the area under the receiver operating characteristic curve from 0.607 to 0.632. Criteria that are based on four clinical or public health applications were used to compare BCRAT with BCRATplus7, which includes the seven genotypes. Criteria included number of expected life-threatening events for the decision to take tamoxifen, expected decision losses (in units of the loss from giving a mammogram to a woman without detectable breast cancer) for the decision to have a mammogram, rates of risk reclassification, and number of lives saved by risk-based allocation of screening mammography. For all calculations, the following assumptions were made: Hardy-Weinberg equilibrium, linkage equilibrium across SNPs, additive effects of alleles at each locus, no interactions on the logistic scale among SNPs or with factors in BCRAT, and independence of SNPs from factors in BCRAT. Improvements in expected numbers of life-threatening events were only 0.07% and 0.81% for deciding whether to take tamoxifen to prevent breast cancer for women aged 50-59 and 40-49 years, respectively. For deciding whether to recommend screening mammograms to women aged 50-54 years, the reduction in expected losses was 0.86% if the ideal breast cancer prevalence threshold for recommending mammography was that of women aged 50-54 years. Cross-classification of risks indicated that some women classified by BCRAT would have different classifications with BCRATplus7, which might be useful if BCRATplus7 was well calibrated. Improvements from BCRATplus7 were small for risk-based allocation of mammograms under costs constraints. The gains from BCRATplus7 are small in the applications examined. Models with SNPs, such as BCRATplus7, have not been validated for calibration in independent cohort data. Additional studies are needed to validate a model with SNPs and justify its use.


Causes, magnitude and management of burns in under-fives in district hospitals in Dar es Salaam, Tanzania.
To determine the causes, magnitude and management of burns in children under five years of age who were admitted in the district hospitals of Dar es Salaam City, Tanzania. In this study, a total of 204 under fives were enrolled. Questionnaires were used to elicit if the parent/caretaker had the knowledge of the cause of the burns, what was done immediately after burn injury, first aid given immediately after burn, source of the knowledge of first aid and when the child was taken to the hospital. Also the questionnaire was cited with data on the management of burns in the hospitals through observation and checking the treatment files. Forty nine percent were males while 50.5% were females. Most of the children (54.9%) were aged between 1-2 years. 78.4% had scalds while 21.6% had flame burns. No children were found to have burns caused by chemicals or electricity. Most of the burns (97.5%) occurred accidentally, although some (2.5%) were intentional. 68.6% of these burn injuries occurred in the kitchen. Immediately after burn 87.3% of the children had first aid applied on their wounds while 12.7% didn't apply anything. Of the agents used, honey was the most used (32.8%) followed by cold water (16.7%). The source of knowledge on these agents was from relatives and friends (72.5%), schools (7%), media (6%) and medical personnel (14%). The study further revealed that analgesics, intravenous fluids, antiseptics and antibiotics were the drugs used for treatment of burns in the hospital and that there was no specialized unit for burns in the hospitals. Causes of childhood burns are largely preventable requiring active social/medical education and public enlighten campaigns on the various methods of prevention. The government to see to it that hospitals have specialized units for managing burn cases and also the socio-economic status of its people be improved.


Low dose naltrexone for induction of remission in Crohn's disease.
Crohn's disease is a transmural, relapsing inflammatory condition afflicting the digestive tract. Opioid signalling, long known to affect secretion and motility in the gut, has been implicated in the inflammatory cascade of Crohn's disease. Low dose naltrexone, an opioid antagonist, has garnered interest as a potential therapy. The primary objective was to evaluate the efficacy and safety of low dose naltrexone for induction of remission in Crohn's disease. A systematic search of MEDLINE, Embase, PubMed, CENTRAL, and the Cochrane IBD Group Specialized Register was performed from inception to 15 January 2018 to identify relevant studies. Abstracts from major gastroenterology conferences including Digestive Disease Week and United European Gastroenterology Week and reference lists from retrieved articles were also screened. Randomized controlled trials of low dose naltrexone (LDN) for treatment of active Crohn's disease were included. Data were analyzed on an intention-to-treat basis using Review Manager (RevMan 5.3.5). The primary outcome was induction of clinical remission defined by a Crohn's disease activity index (CDAI) of < 150 or a pediatric Crohn's disease activity index (PCDAI) of < 10. Secondary outcomes included clinical response (70- or 100-point decrease in CDAI from baseline), endoscopic remission or response, quality of life, and adverse events as defined by the included studies. Risk ratios (RR) and 95% confidence intervals (CI) were calculated for dichotomous outcomes. The methodological quality of included studies was evaluated using the Cochrane risk of bias tool. The overall quality of the evidence supporting the primary outcome and selected secondary outcomes was assessed using the GRADE criteria. Two studies were identified (46 participants). One study assessed the efficacy and safety of 12 weeks of LDN (4.5 mg/day) treatment compared to placebo in adult patients (N = 34). The other study assessed eight weeks of LDN (0.1 mg/kg, maximum 4.5 mg/day) treatment compared to placebo in pediatric patients (N = 12). The primary purpose of the pediatric study was to assess safety and tolerability. Both studies were rated as having a low risk of bias. The study in adult patients reported that 30% (5/18) of LDN treated patients achieved clinical remission at 12 weeks compared to 18% (3/16) of placebo patients, a difference that was not statistically significant (RR 1.48, 95% CI 0.42 to 5.24). The study in children reported that 25% of LDN treated patients achieved clinical remission (PCDAI < 10) compared to none of the patients in the placebo group, although it was unclear if this result was for the randomized placebo-controlled trial or for the open label extension study. In the adult study 70-point clinical response rates were significantly higher in those treated with LDN than placebo. Eighty-three per cent (15/18) of LDN patients had a 70-point clinical response at week 12 compared to 38% (6/16) of placebo patients (RR 2.22, 95% CI 1.14 to 4.32). The effect of LDN on the proportion of adult patients who achieved a 100-point clinical response was uncertain. Sixty-one per cent (11/18) of LDN patients achieved a 100-point clinical response compared to 31% (5/16) of placebo patients (RR 1.96, 95% CI 0.87 to 4.42). The proportion of patients who achieved endoscopic response (CDEIS decline > 5 from baseline) was significantly higher in the LDN group compared to placebo. Seventy-two per cent (13/18) of LDN patients achieved an endoscopic response compared to 25% (4/16) of placebo patients (RR 2.89; 95% CI 1.18 to 7.08). However, there was no statistically significant difference in the proportion of patients who achieved endoscopic remission. Endoscopic remission (CDEIS < 3) was achieved in 22% (4/18) of the LDN group compared to 0% (0/16) of the placebo group (RR 8.05; 95% CI 0.47 to 138.87). Pooled data from both studies show no statistically significant differences in withdrawals due to adverse events or specific adverse events including sleep disturbance, unusual dreams, headache, decreased appetite, nausea and fatigue. No serious adverse events were reported in either study. GRADE analyses rated the overall quality of the evidence for the primary and secondary outcomes (i.e. clinical remission, clinical response, endoscopic response, and adverse events) as low due to serious imprecision (sparse data). Currently, there is insufficient evidence to allow any firm conclusions regarding the efficacy and safety of LDN used to treat patients with active Crohn's disease. Data from one small study suggests that LDN may provide a benefit in terms of clinical and endoscopic response in adult patients with active Crohn's disease. Data from two small studies suggest that LDN does not increase the rate of specific adverse events relative to placebo. However, these results need to be interpreted with caution as they are based on very small numbers of patients and the overall quality of the evidence was rated as low due to serious imprecision. Further randomized controlled trials are required to assess the efficacy and safety of LDN therapy in active Crohn's disease in both adults and children.


Prospective outcome data on 267 unselected adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia confirms superiority of allogeneic transplantation over chemotherapy in the pre-imatinib era: results from the International ALL Trial MRC UKALLXII/ECOG2993.
Prospective data on the value of allogeneic hematopoietic stem cell transplantation (alloHSCT) in Philadelphia chromosome-positive (Ph(+)) acute lymphoblastic leukemia (ALL) are limited. The UKALLXII/ECOG 2993 study evaluated the outcome of assigning alloHSCT with a sibling (sib) or matched unrelated donor (MUD) to patients younger than 55 years of age achieving complete remission (CR). The CR rate of 267 patients, median age 40, was 82%. Twenty-eight percent of patients proceeded to alloHSCT in first CR. Age older than 55 years or a pre-HSCT event were the most common reasons for failure to progress to alloHSCT. At 5 years, overall survival (OS) was 44% after sib alloHSCT, 36% after MUD alloHSCT, and 19% after chemotherapy. After adjustment for sex, age, and white blood count and excluding chemotherapy-treated patients who relapsed or died before the median time to alloHSCT, only relapse-free survival remained significantly superior in the alloHSCT group (odds ratio 0.31, 95% confidence interval 0.16-0.61). An intention-to-treat analysis, using the availability or not of a matched sibling donor, showed 5-year OS to be nonsignificantly better at 34% with a donor versus 25% with no donor. This prospective trial in adult Ph(+) ALL indicates a modest but significant benefit to alloHSCT. This trial has been registered with clinicaltrials.gov under identifier NCT00002514 and as ISRCTN77346223.


Measurement Properties of the SF-MPQ-2 Neuropathic Qualities Subscale in Persons with CRPS: Validity, Responsiveness, and Rasch Analysis.
The purpose of this study was to conduct classical psychometric evaluation and Rasch analysis on the Neuropathic Qualities subscale of the Short-Form McGill Pain Questionnaire-2 utilizing scores from persons with complex regional pain syndrome to consider reliability and person separation, validity (including unidimensionality), and responsiveness in this population. Secondary analysis of longitudinal data from persons with acute complex regional pain syndrome was utilized for analysis of the psychometric properties and fit to the Rasch model of the Neuropathic Qualities subscale. We followed an iterative process of Rasch analysis to evaluate and address data fitting challenges. Repeated measures from 59 persons meeting the Budapest criteria were used for analysis. Both item-total correlations and unidimensionality analyses supported theoretical construct validity; all convergent construct validity hypotheses were also supported. Responsiveness was demonstrated comparing baseline and one-year data at d = 0.92, with a standardized response mean of 0.97. Data were able to fit the Rasch model, but all Neuropathic Qualities items had disordered thresholds that required rescoring. Additionally, local dependency and differential item function were addressed by "bundling," suggesting that no further item reduction would be possible. This study provided preliminary support for the validity and responsiveness of the Neuropathic Qualities subscale in persons with complex regional pain syndrome. Rasch analysis further endorses use of the Neuropathic Qualities subscale as a "stand-alone" measure for neuropathic features, but with substantial background data transformations. Replication with larger samples is recommended to increase confidence in these findings.


Symptomatic Diverticulosis Is Characterized By Loose Stools.
Symptomatic uncomplicated diverticular disease is considered to be a discreet clinical entity distinct from irritable bowel syndrome (IBS), but population-based data are unavailable. We aimed to investigate the prevalence and location of diverticulosis in the general population, and its association with colonic symptoms and mental health. We propose that individuals with diverticulosis would report more constipation and IBS. We performed a population-based study of randomly selected adults born in Sweden (age, 18-70 y; 57.2% women); 745 received a gastroenterology consultation, completed validated abdominal symptom and mental health questionnaires, and were examined by colonoscopy. Logistic regression was used to calculate the associations between diverticulosis and age, sex, gastrointestinal symptoms, anxiety, depression, and self-rated health. Among the 742 participants (54.6% women), 130 (17.5%) had diverticulosis. Age was the strongest predictor of diverticulosis (P < .001), and diverticulosis was rare in participants younger than 40 years (0.7%). All participants with diverticulosis had sigmoid involvement. Participants with diverticulosis were more likely to report loose stools (odds ratio [OR], 1.88; 95% confidence interval [CI], 1.20-2.96), urgency (OR, 1.64; 95% CI, 1.02-2.63), passing mucus (OR, 2.26; 95% CI, 1.08-4.72), and a high stool frequency (OR, 2.02; 95% CI, 1.11-3.65). Diverticulosis was associated with abdominal pain (OR, 2.10; 95% CI, 1.01-4.36; P = .047) and diarrhea-predominant IBS (OR, 9.55; 95% CI, 1.08-84.08; P = .04) in participants older than 60 years. The presence of anxiety and depression and self-rated health were similar in participants with and without diverticulosis. The prevalence of diverticulosis is age-dependent. Diverticulosis is associated with diarrhea in subjects across all age ranges. In subjects older than age 60, diverticulosis is associated with abdominal pain and diarrhea-predominant IBS.


Luminescence and white-light emitting luminescent sensor of tetrafluoroterephthalate-lanthanide metal-organic frameworks.
Two types of sixteen complexes 1-16, namely, {[Ln(TFBDC)1.5(H2O)]·2H2O}n [Ln = Pr (1) and Nd (2)] and {[Ln(TFBDC)1.5(H2O)2]·H2O}n [Ln = Ce (3), Pr (4), Nd (5), Sm (6), Eu (7), Gd (8), Tb (9), Dy (10), Ho (11), Er (12), Yb (13) and Lu (14)], {[Dy0.281Eu0.719(TFBDC)1.5(H2O)2]·H2O}n (15) and {[Gd0.871Eu0.103Tb0.026(TFBDC)1.5(H2O)2]·H2O}n (16), were isolated by the reaction of LnCl3·6H2O with 2,3,5,6-tetrafluoroterephthalic acid (H2TFBDC). X-ray crystallographic analysis revealed that 1 and 2 exhibit 3D network structures and complexes 3-14 feature 2D network structures formed via three different coordination modes of the ligand. Luminescence spectra revealed that these complexes exhibit broad-spectrum luminescence from the visible to the near-infrared (NIR) region. Unexpectedly, complex 1 exhibits a unique NIR luminescence pattern and the longest lifetime among reported molecular praseodymium complexes. White-light emission was realized via three approaches using the single-component complex 6 (Sm), the two-component complex 15 (Eu and Dy) and the three-component complex 16 (Eu, Tb and Gd). Complex 9 exhibits high sensitivity and selectivity in its luminescence response to benzaldehyde, which provides a promising luminescent sensor for the detection of benzaldehyde.


Comparison of three hypothermic target temperatures for the treatment of hypoxic ischemia: mRNA level responses of eight genes in the piglet brain.
Hypothermia can reduce neurodevelopmental disabilities in asphyxiated newborn infants. However, the optimal cooling temperature for neuroprotection is not well defined. We studied the effects of transient piglet brain hypoxic ischemia (HI) on transcriptional activity of eight genes and if mRNA level alterations could be counteracted by whole body cooling to 35, 33.5 or 30 °C. BDNF mRNA was globally upregulated by the insult, and none of the cooling temperatures counteracted this change. In contrast, MANF mRNA was downregulated, and these changes were modestly counteracted in different brain regions by hypothermic treatment at 33.5 °C, while 30 °C aggravated the MANF mRNA loss. MAP2 mRNA was markedly downregulated in all brain regions except striatum, and cooling to 33.5 °C modestly counteract this downregulation in the cortex cerebri. There was a tendency for GFAP mRNA levels in core, but not mantle regions to be downregulated and for these changes to be modestly counteracted by cooling to 33.5 or 35 °C. Cooling to 30 °C caused global GFAP mRNA decrease. HSP70 mRNA tended to become upregulated by HI and to be more pronounced in cortex and CA1 of hippocampus during cooling to 33.5 °C. We conclude that HI causes alterations of mRNA levels of many genes in superficial and deep piglet brain areas. Some of these changes may be beneficial, others detrimental, and lowering body temperature partly counteracts some, but not all changes. There may be general differences between core and mantle regions, as well as between the different cooling temperatures for protection. Comparing the three studied temperatures, cooling to 33.5 °C, appears to provide the best cooling temperature compromise.


Effect of material variation on the biomechanical behaviour of orthodontic fixed appliances: a finite element analysis.
Biomechanical analysis of orthodontic tooth movement is complex, as many different tissues and appliance components are involved. The aim of this finite element study was to assess the relative effect of material alteration of the various components of the orthodontic appliance on the biomechanical behaviour of tooth movement. A three-dimensional finite element solid model was constructed. The model consisted of a canine, a first, and a second premolar, including the surrounding tooth-supporting structures and fixed appliances. The materials of the orthodontic appliances were alternated between: (1) composite resin or resin-modified glass ionomer cement for the adhesive, (2) steel, titanium, ceramic, or plastic for the bracket, and (3) β-titanium or steel for the wire. After vertical activation of the first premolar by 0.5mm in occlusal direction, stress and strain calculations were performed at the periodontal ligament and the orthodontic appliance. The finite element analysis indicated that strains developed at the periodontal ligament were mainly influenced by the orthodontic wire (up to +63 per cent), followed by the bracket (up to +44 per cent) and the adhesive (up to +4 per cent). As far as developed stresses at the orthodontic appliance are concerned, wire material had the greatest influence (up to +155 per cent), followed by bracket material (up to +148 per cent) and adhesive material (up to +8 per cent). The results of this in silico study need to be validated by in vivo studies before they can be extrapolated to clinical practice. According to the results of this finite element study, all components of the orthodontic fixed appliance, including wire, bracket, and adhesive, seem to influence, to some extent, the biomechanics of tooth movement.


New cell surface antigens in rat defined by tumors of the nervous system.
Tumors of the central and peripheral nervous system were induced in rats with ethylnitrosourea. Many of these tumors were transplanted in syngeneic recipients, and several cell lines were derived from them. An antiserum raised against one such cell line in C3H mice defined two cell surface antigens in cytotoxicity tests. One, the common antigen, was present on rat brain and embryonic tissues and was present in large amounts on most tumors or cell lines from the nervous system. Fibroblastic cell lines had smaller amounts of this antigen, which also could be detected by immunofluorescence. The other, restricted antigen was not detected on normal or other, restricted antigen was not detected on normal or embryonic tissues. It was present on six tumors from the nervous system, on one glial cell line, and on a Schwann-cell line RN22. In addition, it was present on four out of eleven cloned cell lines isolated from rat tumors at the Salk Institute. Two of the positive clonal lines had been shown to have properties unique to neuronal cells. The restricted antigen was therefore expressed on the cell surface of some, but not all, glial, Schwann, and neuronal neoplastic cells.


Engineering the polyphenolic biosynthetic pathway stimulates metabolic and molecular changes during fruit ripening in "Bronze" tomato.
The metabolic engineered Bronze tomato line is characterized by the constitutive over-expression of the VvStSy gene encoding a structural protein responsible for the stilbenoids biosynthesis and the fruit-specific over-expression of AmDel/Rosea1 and AtMYB12 genes encoding transcription factors that activate the polyphenol biosynthetic pathway. This tomato line is known for the increased levels of polyphenols in ripe fruits and for beneficial health promoting antioxidant and anti-inflammatory effects. In this study we analyzed the transcriptional and metabolic profiling in mature green, breaker, orange and ripe fruits compared to the normal tomato counterparts during ripening, to unravel the effect of regulatory and structural transgenes on metabolic fluxes of primary and secondary metabolisms. Our results showed that the shikimate synthase (SK) gene was up-regulated in the Bronze fruit, and the transcriptional activation is consistent with the metabolic changes observed throughout fruit ripening. These results paralleled with a reduced level of simple sugars and malate, highlighting the consumption of primary metabolites to favor secondary metabolites production and accumulation. Finally, carotenoids quantification revealed a change in the lycopene/β-carotene ratio in the Bronze fruit as a consequence of significant lower level of the first and higher levels of the latter. The high polyphenols and β-carotene content displayed by the Bronze fruit at the later stages of fruit ripening renders this line an interesting model to study the additive or synergic effects of these phyto-chemicals in the prevention of human pathologies.


Patterns of involvement with malignant lymphoma and implications for treatment decision making.
Decision making in cancer therapy has traditionally evolved through careful observation of the clinical course subsequent to various treatment approaches. This method has also served to delineate the wide spectrum of primary manifestations and patterns of biological behaviour characterizing the malignant lymphomata. Marked disparity has been consistently appreciated between the natural history of lymphomata originating in lymph nodes in contrast to those primary in extranodal sites. The former are usually anatomically generalized at diagnosis whereas primary extranodal lymphomata are commonly localized and more closely resemble carcinomata of the respective organs with their propensity for both regional lymphatic extension and haematogenous spread. Prospective staging of 100 consecutive patients with previously untreated malignant lymphoma has been consistent with this past experience in demonstrating the presence of disseminated involvement in the majority of patients. It has also become apparent that reliance upon either clinical or surgical staging of disease extent is often misleading since widespread disease frequently develops even in those patients staged as having localized involvement and thereby treated with local irradiation. High dose, wide field lymphatic irradiation "á la Hodgkin's disease" seldom constitutes appropriate treatment for patients having lymph node presentations of lymphoma. There is rather a need to recognize the importance of systemic treatment for most cases, negating the utility of routine exhaustive staging since treatment decisions can be based upon readily assessed clinicohistological determinants in the majority of cases.


The Werner syndrome protein promotes CAG/CTG repeat stability by resolving large (CAG)(n)/(CTG)(n) hairpins.
Expansion of CAG/CTG repeats causes certain neurological and neurodegenerative disorders, and the formation and subsequent persistence of stable DNA hairpins within these repeats are believed to contribute to CAG/CTG repeat instability. Human cells possess a DNA hairpin repair (HPR) pathway, which removes various (CAG)(n) and (CTG)(n) hairpins in a nick-directed and strand-specific manner. Interestingly, this HPR system processes a (CTG)(n) hairpin on the template DNA strand much less efficiently than a (CAG)(n) hairpin on the same strand (Hou, C., Chan, N. L., Gu, L., and Li, G. M. (2009) Incision-dependent and error-free repair of (CAG)(n)/(CTG)(n) hairpins in human cell extracts. Nat. Struct. Mol. Biol. 16, 869-875), suggesting the involvement of an additional component for (CTG)(n) HPR. To identify this activity, a functional in vitro HPR assay was used to screen partially purified HeLa nuclear fractions for their ability to stimulate (CTG)(n) HPR. We demonstrate here that the stimulating activity is the Werner syndrome protein (WRN). Although WRN contains both a 3'→5' helicase activity and a 3'→5' exonuclease activity, the stimulating activity was found to be the helicase activity, as a WRN helicase mutant failed to enhance (CTG)(n) HPR. Consistently, WRN efficiently unwound large (CTG)(n) hairpins and promoted DNA polymerase δ-catalyzed DNA synthesis using a (CTG)(n) hairpin as a template. We, therefore, conclude that WRN stimulates (CTG)(n) HPR on the template DNA strand by resolving the hairpin so that it can be efficiently used as a template for repair or replicative synthesis.


Incidence and duration of breastfeeding for term infants in Canada, United States, Europe, and Australia: a literature review.
Analysis of differences in the incidence and duration of breastfeeding across countries may provide information about practices that encourage breastfeeding. This comparative review examines variation in the incidence and duration of breastfeeding for term infants that has been reported in studies from Canada, the United States, Europe, and Australia. Searches were conducted in PubMed, MEDLINE (from 1966), CINHAL (from 1982), and the Cochrane Database of Systematic Reviews. Studies were limited to nonexperimental and observational research that addressed term infants (>37 weeks gestational age), performed in developed countries, written in the English language, and published since 1990. Additional studies were located from reference lists of meta-analyses, systematic reviews, and previous articles. All studies that met study criteria were included in the review, regardless of the quality of methodology. Although studies had methodological limitations that precluded conducting a formal systematic review or meta-analysis, this comparative review revealed consistent differences among countries. For example, Europe and Australia reported a higher initiation and duration of breastfeeding term infants compared with Canada and the United States. Studies that examined reasons for a higher incidence and duration of breastfeeding term infants consistently document that women who initiate and continue to breastfeed are older, married, better educated, and have higher family incomes than women who do not breastfeed.


A computerized analysis-by-synthesis algorithm improves precision of linear wear measurements in total hip replacements.
Precision is important if small polyethylene wear rates are to be detected early and in small sample sizes. Using an automatic, computerized algorithm relying on a synthetic X-ray generated from a computer-assisted design (CAD) model of the implant may significantly improve precision of linear wear measurements. We compared this method to provide improved in vivo precision compared to the widely used Hip Analysis Suite software (version 188.8.131.52). Two anterior-posterior pelvic X-rays were taken on the same day of 18 total hip implants, and wear was measured by three observers using the two methods. Expected real wear was zero and defined as a reference value. Two sources of variability were estimated: one due to the instrument, and one due to different operators. A Wilcoxon Signed Rank Test was used for statistical comparisons. The overall precision (instrument variability and multioperator variability) given a 95% precision limit was significantly higher (p < 0.001) using the proposed method (+/-0.15 mm) when compared to the Hip Analysis Suite (+/-0.84 mm). Due to the availability of the full CAD data of the implant and to further automation of the measuring process, the newly proposed method provided improved precision in measuring polyethylene wear.


Superantigens: microbial agents that corrupt immunity.
Microbial superantigens are a family of protein exotoxins that share the ability to trigger excessive and aberrant activation of T cells. The best characterised are the staphylococcal enterotoxins and the streptococcal pyrogenic exotoxins that trigger the staphylococcal and streptococcal toxic shock syndromes. It is now apparent that superantigens have a wider role in the pathology of infectious diseases than has previously been appreciated. Staphylococcus aureus and Streptococcus pyogenes together produce 19 different superantigens. The range of microorganisms known to produce superantigens has expanded to include Gram negative bacteria, mycoplasma, and viruses. Research is beginning to shed light on the more subtle parts these molecules play in causing disease and to produce some real possibilities for specific treatment of superantigen-induced toxicity. We aim to highlight these new developments and review the science behind these fascinating molecules.


Thermal unfolding of the archaeal DNA and RNA binding protein Ssh10.
The reversible thermal unfolding of the archaeal histone-like protein Ssh10b from the extremophile Sulfolobus shibatae was studied using differential scanning calorimetry and circular dichroism spectroscopy. Analytical ultracentrifugation and gel filtration showed that Ssh10b is a stable dimer in the pH range 2.5-7.0. Thermal denaturation data fit into a two-state unfolding model, suggesting that the Ssh10 dimer unfolds as a single cooperative unit with a maximal melting temperature of 99.9 degrees C and an enthalpy change of 134 kcal/mol at pH 7.0. The heat capacity change upon unfolding determined from linear fits of the temperature dependence of DeltaH(cal) is 2.55 kcal/(mol K). The low specific heat capacity change of 13 cal/(mol K residue) leads to a considerable flattening of the protein stability curve (DeltaG (T)) and results in a maximal DeltaG of only 9.5 kcal/mol at 320 K and a DeltaG of only 6.0 kcal/mol at the optimal growth temperature of Sulfolobus.


Ultrafast Continuum IR Generation and Its Application in IR Spectroscopy.
The spectral range of femtosecond time-resolved infrared spectroscopy is limited by the bandwidth of mid-IR pulses (100~400 cm-1) generated from the combination of Ti:Sapphire amplifier, Optical Parametric Amplifier (OPA), and Difference Frequency Generation (DFG). To overcome this limitation, we implement a compact continuum mid-IR source producing ultrafast pulses that span the frequency range from 1000 to 4200 cm-1 (from 10 to 2.4 μm), which utilize the mixing of fundamental, second-harmonic, and third-harmonic of 800 nm pulse in the air. After building an IR spectrometer with continuum IR and a monochromator, we found that the distortion of the measured IR spectrum originated from the contamination of higher-order diffraction. We used bandpass filters to eliminate the higher-order contributions and correct the measured IR spectrum. We further characterized the spectral properties of fundamental, second-harmonic, and third-harmonic fields after the plasmonic filamentation process, which helps to improve the efficiency of the continuum IR generation. Using the generated continuum IR pulses, we measured the IR absorption spectrum of a water-benzonitrile mixture, which was found to be consistent with the spectrum obtained with a commercial FT-IR spectrometer. The present work will be useful for the efficient generation of continuum IR pulses for IR pump-probe and two-dimensional IR spectroscopy experiments in the future.


Use of home blood pressure monitoring and exercise, diet and medication compliance in Japan.
Little is known about the attitudes of doctors and patients to the use of home blood pressure monitoring (HBPM) and its relationship with compliance to exercise, diet, and antihypertensive medication and blood pressure (BP) control. We conducted a cross-sectional internet survey in treated patients with hypertension in Japan. Overall, 500 questionnaires were returned; 292 respondents (58.4%) reported that their doctor had recommended HBPM and among them 106 (36.3%) reported satisfactory adherence to HBPM. Compared to patients with poor adherence to HBPM, patients with satisfactory adherence to HBPM were more likely to have satisfactory compliance with exercise, diet and medication but no significant difference in BP control.


Determination of risk factors for predicting the onset of symptoms in asymptomatic COVID-19 infected patients.
Background: The number of asymptomatic infected patients with coronavirus disease 2019 (COVID-2019) is rampaging around the world but limited information aimed on risk factors of asymptomatic infections. The purpose of this study is to investigate the risk factors of symptoms onset and clinical features in asymptomatic COVID-19 infected patients. Methods: A retrospective study was performed in 70 asymptomatic COVID-2019 infected patients confirmed by nucleic acid tests in Hunan province, China between 28 January 2020 and 18 February, 2020. The epidemiological, clinical features and laboratory data were reviewed and analyzed. Presence or absence at the onset of symptoms was taken as the outcome. A Cox regression model was performed to evaluate the potential predictors of the onset of symptoms. Results: The study included 36 males and 34 females with a mean age of 33.24±20.40 years (range, 0.5-84 years). There were 22 asymptomatic carriers developed symptoms during hospitalization isolated observation, and diagnosed as confirmed cases, while 48 cases remained asymptomatic throughout the course of disease. Of 70 asymptomatic patients, 14 (14/70, 20%) had underlying diseases, 3 (3/70, 4.3%) had drinking history, and 11 (11/70, 15.7%) had smoking history. 22 patients developed symptoms onset of fever (4/22, 18.2%), cough (13/22, 59.1%), chest discomfort (2/22, 9.1%), fatigue (1/22, 4.5%), pharyngalgia (1/22, 4.5%) during hospitalization; only one (1/22, 4.5%) patient developed signs of both cough and pharyngalgia. Abnormalities on chest CT were detected among 35 of the 69 patients (50.7%) after admission, except for one pregnant woman had not been examined. 4 (4/70, 5.7%) and 8 (8/70, 11.4%) cases showed leucopenia and lymphopenia. With the effective antiviral treatment, all the 70 asymptomatic infections had been discharged, none cases developed severe pneumonia, admission to intensive care unit, or died. The mean time from nucleic acid positive to negative was 13.2±6.84 days. Cox regression analysis showed that smoking history (P=0.028, hazard ratio=4.49, 95% CI 1.18-17.08) and existence of pulmonary disease (P=0.038, hazard ratio=7.09, 95% CI 1.12-44.90) were risk factors of the onset of symptoms in asymptomatic carries. Conclusion: The initially asymptomatic patients can develop mild symptoms and have a good prognosis. History of smoking and pulmonary disease was prone to illness onset in asymptomatic patients, and it is necessary to be highly vigilant to those patients.


Unequivocal determination of caulamidines A and B: application and validation of new tools in the structure elucidation tool box.
Ambiguities and errors in the structural assignment of organic molecules hinder both drug discovery and total synthesis efforts. Newly described NMR experimental approaches can provide valuable structural details and a complementary means of structure verification. The caulamidines are trihalogenated alkaloids from a marine bryozoan with an unprecedented structural scaffold. Their unique carbon and nitrogen framework was deduced by conventional NMR methods supplemented by new experiments that define 2-bond heteronuclear connectivities, reveal very long-range connectivity data, or visualize the 35,37Cl isotopic effect on chlorinated carbons. Computer-assisted structural elucidation (CASE) analysis of the spectroscopic data for caulamidine A provided only one viable structural alternative. Anisotropic NMR parameters, specifically residual dipolar coupling and residual chemical shift anisotropy data, were measured for caulamidine A and compared to DFT-calculated values for the proposed structure, the CASE-derived alternative structure, and two energetically feasible stereoisomers. Anisotropy-based NMR experiments provide a global, orthogonal means to verify complex structures free from investigator bias. The anisotropic NMR data were fully consistent with the assigned structure and configuration of caulamidine A. Caulamidine B has the same heterocyclic scaffold as A but a different composition and pattern of halogen substitution. Caulamidines A and B inhibited both wild-type and drug-resistant strains of the malaria parasite Plasmodium falciparum at low micromolar concentrations, yet were nontoxic to human cells.


Translocator protein 18 kDa (TSPO) is regulated in white and brown adipose tissue by obesity.
Translocator protein 18 kDa (TSPO) is an outer-mitochondrial membrane transporter which has many functions including participation in the mitochondrial permeability transition pore, regulation of reactive oxygen species (ROS), production of cellular energy, and is the rate-limiting step in the uptake of cholesterol. TSPO expression is dysregulated during disease pathologies involving changes in tissue energy demands such as cancer, and is up-regulated in activated macrophages during the inflammatory response. Obesity is associated with decreased energy expenditure, mitochondrial dysfunction, and chronic low-grade inflammation which collectively contribute to the development of the Metabolic Syndrome. Therefore, we hypothesized that dysregulation of TSPO in adipose tissue may be a feature of disease pathology in obesity. Radioligand binding studies revealed a significant reduction in TSPO ligand binding sites in mitochondrial extracts from both white (WAT) and brown adipose tissue (BAT) in mouse models of obesity (diet-induced and genetic) compared to control animals. We also confirmed a reduction in TSPO gene expression in whole tissue extracts from WAT and BAT. Immunohistochemistry in WAT confirmed TSPO expression in adipocytes but also revealed high-levels of TSPO expression in WAT macrophages in obese animals. No changes in TSPO expression were observed in WAT or BAT after a 17 hour fast or 4 hour cold exposure. Treatment of mice with the TSPO ligand PK11195 resulted in regulation of metabolic genes in WAT. Together, these results suggest a potential role for TSPO in mediating adipose tissue homeostasis.


Socio-economic gradients in maternal and child health-seeking behaviours in egypt: systematic literature review and evidence synthesis.
Health-seeking behaviour lies on the direct pathway between socio-economic position (SEP) and health outcomes. The objective of this systematic review is to identify and synthesise evidence of socio-economic gradients in health-seeking behaviours related to maternal and child health in Egypt. Four databases (Medline, Embase, Global Health and Web of Science) were searched in September 2013 for material published in English from 1992 to 2013 for a combination of terms describing health-seeking behaviours, indicators of socio-economic position and geographical limitation to Egypt. Findings of studies were described and synthesised in a narrative format as meta-analysis was not possible. Among the 786 references identified, 10 articles met the inclusion criteria. Six studies examined maternal and five studies child health-seeking behaviours (one study examined both). For maternal health, three dimensions of health-seeking behaviour (receipt of any care, type of care and intensity of care) were covered by studies of ante-natal and one dimension (type of care) by analyses of delivery care. For child health, two dimensions of preventive care (coverage of and intensity of immunisation) and three dimensions of curative care (receipt of any care, type and cost of care) were analysed. Based on two studies of time trends in nationally-representative surveys, socio-economic inequalities in seeking care for basic preventive and curative interventions in maternal and child health appear to have narrowed. Limited evidence of gradients in intensity of maternal preventive and provider selection in child curative care showed that inequalities may have widened. In studies of more geographically and socially homogeneous samples, fewer gradients were identified. Current body of evidence contains numerous limitations and gaps and is insufficient to draw a conclusive summary of such gradients. Improved understanding of SEP gradients is crucial in designing and prioritising interventions to equitably improve maternal and child health outcomes.


Why is Pseudosphromenus cupanus (Teleostei: Osphronemidae) reported from Bangladesh, Indonesia, Malaysia, Myanmar, and Pakistan?
The native distribution of the small labyrinth fish species Pseudosphromenus cupanus includes southern India and Sri Lanka. According to literature it has a range including also Pakistan, Bangladesh, Myanmar, Malaysia, and Indonesia (Sumatra) but there are no voucher specimens or reliable observations from those areas. The distribution record of P. cupanus was inflated partly by including P. dayi as a synonym. Pseudosphronemus dayi is native to the Western Ghats in India, but the origin of the aquarium importation in 1907 was reported as both Cochin (=Kochi) and Malacca (=Malaysia), the latter locality obviously in error. The basis for the Sumatra record is an obviously mislabeled sample of P. dayi from Pulau Weh close to Sumatra. The basis for reporting the species from Pakistan, Myanmar or Bangladesh could not be located. Misidentified museum specimens from Myanmar and Pakistan identified as P. cupanus were never published on. Pseudosphromenus cupanus has been considered recently to be extinct in Bangladesh, but in fact it never occurred there.