Pathogenesis of human strongyloidiasis: autopsy and quantitative parasitological analysis.
The distribution of pathologic lesions and the parasite burden of major organs were studied in seven patients with disseminated strongyloidiasis who were autopsied at the University of Texas Medical Branch (Galveston, TX). All patients were immunosuppressed and had additional bacterial, viral, and fungal infections; six patients had received cortisone therapy and one patient had AIDS. High Strongyloides burdens were noted in untreated patients or in those with a short period of treatment. The proximal small intestine and the lungs showed the heaviest parasite burden, with large numbers of filariform larvae found in both locations. The lungs showed persistence of larvae in all patients, in the absence of intestinal or extraintestinal infection; this suggests that the respiratory cycle may be more resistant to therapy than the intestinal cycle. In the intestines, filariform larvae were seen at all levels, but higher burdens were seen in the upper as compared to lower small intestine, and larvae were more concentrated in the proximal jejunum than in the duodenum. Autoinfection (i.e., filariform larval penetration) occurred more prominently in the distal small and proximal large intestine than in the distal colon. Most filariform larvae were found in the intestinal lymphatics and were highly concentrated in mesenteric and retroperitoneal lymph nodes; conversely, larvae were not found in the spleen and were found in very low density in the liver. These findings, in concert, suggest that during autoinfection in humans, the Stronglyloides larvae transverse lymphatics to the thoracic duct, then pursue a lymphohematogenous dissemination to the lungs where they penetrate the air spaces and ascend through the airways to reach the gut.


Childhood autism spectrum disorder: insights from a tertiary hospital cohort in Kenya.
Autism spectrum disorder (ASD) is characterized by impairments in behavior, social communication, and interaction. There is little data on ASD from sub-Saharan Africa (SSA) describing clinical characteristics in large cohorts of patients. Preliminary studies report a high male sex ratio, excess of nonverbal cases, possible infectious etiologies, and comorbidities e.g. epilepsy. To describe the clinical characteristics of children diagnosed with ASD in an African context. A retrospective medical chart review identified 116 children diagnosed with ASD according to DSM-5 criteria at a pediatric neurology clinic in Nairobi, Kenya. The male to female ratio was 4.3:1. The median age at presentation was 3 years with speech delay as the most common reason for presentation. Expressive language delay was observed in 90% of the population. Sixty percent who obtained imaging had normal MRI brain findings. Only 44% and 34% of children had access to speech therapy and occupational therapy respectively. Epilepsy and ADHD were the most prevalent comorbidities. An early median age at presentation and preponderance of male gender is observed. Access to speech therapy and other interventions was low. A prospective study would help determine outcomes for similar children following appropriate interventions.


Do therapist behaviors differ with Hispanic youth? A brief look at within-session therapist behaviors and youth treatment response.
Brief addiction treatments, including motivational interviewing (MI), have shown promise with youth. One underexamined factor in this equation is the role of therapist behaviors. We therefore sought to assess whether and how therapist behaviors differ for Hispanic versus non-Hispanic youth and how that may be related to treatment outcome. With 80 substance-using adolescents (M age = 16 years; 65% male; 59% Hispanic; 41% non-Hispanic), we examined the relationship between youth ethnicity and therapist behaviors across two brief treatments (MI and alcohol/marijuana education [AME]). We then explored relationships to youth 3-month treatment response across four target outcomes: binge drinking days, alcohol-related problems, marijuana use days, and marijuana-related problems. In this study, therapists showed significantly more MI skills within the MI condition and more didactic skills in the AME condition. With respect to youth ethnicity, across both conditions (MI and AME), therapists used less MI skills with Hispanic youth. Contrary to expectations, therapists' use of MI skills was not connected to poorer outcomes for Hispanic youth across the board (e.g., for binge drinking days, marijuana use days, or marijuana-related problems). Rather, for Hispanic youth, therapists' use of lower MI skills was related only to poorer treatment outcomes in the context of alcohol-related problems. The observed relationships highlight the importance of investigating salient treatment interactions between therapist factors and youth ethnicity to guide improvements in youth treatment response.


Interannual variation of springtime biomass burning in Indochina: Regional differences, associated atmospheric dynamical changes, and downwind impacts.
During March and April, widespread burning occurs across farmlands in Indochina in preparation for planting at the monsoon onset. The resultant aerosols impact the air quality downwind. In this study, we investigate the climatic aspect of the interannual variation of springtime biomass burning in Indochina and its correlation with air quality at Mt. Lulin in Taiwan using long-term (2005-2015) satellite and global reanalysis data. Based on empirical orthogonal function (EOF) analysis, we find that the biomass burning activities vary with two geographical regions: northern Indochina (the primary EOF mode) and southern Indochina (the secondary EOF mode). We determine that the variation of biomass burning over northern Indochina is significantly related with the change in aerosol concentrations at Mt. Lulin. This occurs following the change in the so-called India-Burma Trough in the lower and middle troposphere. When the India-Burma Trough is intensified, a stronger northwesterly wind (to the west of the trough) transports the dryer air from higher latitude into northern Indochina, and this promotes local biomass burning activities. The increase in upward motion to the east of the intensified India-Burma Trough lifts the aerosols, which are transported toward Taiwan by the increased low-level westerly jet. Further diagnoses revealed the connection between the India-Burma Trough and the South Asian jet's wave train pattern as well as the previous winter's El Niño-Southern Oscillation phase. This information highlights the role of the India-Burma Trough in modulating northern Indochina biomass burning and possibly predicting aerosol transport to East Asia on the interannual time scale.


Involvement of SMARCA2/BRM in the SWI/SNF chromatin-remodeling complex in schizophrenia.
Chromatin remodeling may play a role in the neurobiology of schizophrenia and the process, therefore, may be considered as a therapeutic target. The SMARCA2 gene encodes BRM in the SWI/SNF chromatin-remodeling complex, and associations of single nucleotide polymorphisms (SNPs) to schizophrenia were found in two linkage disequilibrium blocks in the SMARCA2 gene after screening of 11 883 SNPs (rs2296212; overall allelic P = 5.8 x 10(-5)) and subsequent screening of 22 genes involved in chromatin remodeling (rs3793490; overall allelic P = 2.0 x 10(-6)) in a Japanese population. A risk allele of a missense polymorphism (rs2296212) induced a lower nuclear localization efficiency of BRM, and risk alleles of intronic polymorphisms (rs3763627 and rs3793490) were associated with low SMARCA2 expression levels in the postmortem prefrontal cortex. A significant correlation in the fold changes of gene expression from schizophrenic prefrontal cortex (from the Stanley Medical Research Institute online genomics database) was seen with suppression of SMARCA2 in transfected human cells by specific siRNA, and of orthologous genes in the prefrontal cortex of Smarca2 knockout mice. Smarca2 knockout mice showed impaired social interaction and prepulse inhibition. Psychotogenic drugs lowered Smarca2 expression while antipsychotic drugs increased it in the mouse brain. These findings support the existence of a role for BRM in the pathophysiology of schizophrenia.


[Nutritional status of adolescents and its relation with socio-demographics variables: National Adolescent School-based Health Survey (PeNSE), 2009].
The aim of this study was to describe the nutritional status of adolescents in the 9th year of public and private schools of the Brazilian capitals and its association with socio-demographic variables. By means of a self-completed questionnaire, information related to sex, race, age, public/private school, macro-region of the country, maternal education and family possessions were recorded. Measures of weight and height were measured according to standardized procedures. Height for age and body mass index for age was evaluated according to the World Health Organization reference. Anthropometric measurements of 58,971 adolescents were obtained, of which 2.9% were stunted and 2.9% underweight. There was 23.0% of overweight and 7.3% of obesity, which were higher in the South and Southeast regions. Deficits in height and weight, overweight and obesity were more prevalent in boys. The deficits were higher at public schools while overweight and obesity at private ones. Adolescents whose mothers were less educated or from poorer families had greater deficits in height and the reverse occurred with overweight and obesity. The findings about the deficits, overweight and obesity highlight the need for nutritional interventions designed to reach this stage of life.


The antimicrobial resistance profile of Streptococcus pneumoniae.
Antibacterial resistance in pneumococci is increasing worldwide, primarily against beta-lactams and macrolides. Understanding the role played by molecular determinants of resistance, transformation and competence in the evolution of Streptococcus pneumoniae is important in addressing this trend. Data from the Prospective Resistant Organism Tracking and Epidemiology for the Ketolide Telithromycin (PROTEKT) study indicate that about 40% of pneumococci display multidrug-resistant phenotypes (resistance to three or more antibiotics), with highly variable prevalence rates observed in different countries. Alterations in the structure of six penicillin-binding proteins (PBPs) have been described in S. pneumoniae (1a, 1b, 2x, 2a, 2b and 3), enabling resistance to beta-lactam antibiotics. Mechanisms conferring macrolide resistance include resistance mediated through the erm(B) gene, which results in macrolide-lincosamide-streptogramin B resistance, or through the mef(A) gene, which encodes an antibiotic efflux pump. Another variant, mef(E), is also expressed in S. pneumoniae; both mef(A) and mef(E) variants are associated with strains belonging to serotype 14. In addition to the selection pressure resulting from misuse of antibiotics, widespread vaccination programmes may contribute to changing pneumococcal epidemiology. Since the introduction of the seven-valent pneumococcal conjugate vaccine (PCV7), the rate of invasive pneumococcal disease due to PCV7 serotypes has declined significantly in many countries, but some countries have reported an increase in non-PCV7 serotypes. This phenomenon, termed 'replacement', is associated with certain pneumococcal serotypes or clones (e.g. serotype 19A). Whether novel 'vaccine escape recombinant' pneumococcal strains are emerging or changes in distribution are part of a secular cycle remains to be determined.


The clinical features of polymerase proof-reading associated polyposis (PPAP) and recommendations for patient management.
Pathogenic germline exonuclease domain (ED) variants of POLE and POLD1 cause the Mendelian dominant condition polymerase proof-reading associated polyposis (PPAP). We aimed to describe the clinical features of all PPAP patients with probably pathogenic variants. We identified patients with a variants mapping to the EDs of POLE or POLD1 from cancer genetics clinics, a colorectal cancer (CRC) clinical trial, and systematic review of the literature. We used multiple evidence sources to separate ED variants into those with strong evidence of pathogenicity and those of uncertain importance. We performed quantitative analysis of the risk of CRC, colorectal adenomas, endometrial cancer or any cancer in the former group. 132 individuals carried a probably pathogenic ED variant (105 POLE, 27 POLD1). The earliest malignancy was colorectal cancer at 14. The most common tumour types were colorectal, followed by endometrial in POLD1 heterozygotes and duodenal in POLE heterozygotes. POLD1-mutant cases were at a significantly higher risk of endometrial cancer than POLE heterozygotes. Five individuals with a POLE pathogenic variant, but none with a POLD1 pathogenic variant, developed ovarian cancer. Nine patients with POLE pathogenic variants and one with a POLD1 pathogenic variant developed brain tumours. Our data provide important evidence for PPAP management. Colonoscopic surveillance is recommended from age 14 and upper-gastrointestinal surveillance from age 25. The management of other tumour risks remains uncertain, but surveillance should be considered. In the absence of strong genotype-phenotype associations, these recommendations should apply to all PPAP patients.


Claims for fertility interventions: a systematic assessment of statements on UK fertility centre websites.
Fertility services in the UK are offered by over 200 Human Fertilisation and Embryology Authority (HFEA)-registered NHS and private clinics. While in vitro fertilisation (IVF) and intracytoplasmic sperm injection (ICSI) form part of the National Institute for Health and Care Excellence (NICE) guidance, many further interventions are offered. We aimed to record claims of benefit for interventions offered by fertility centres via information on the centres' websites and record what evidence was cited for these claims. We obtained from HFEA a list of all UK centres providing fertility treatments and examined their websites. We listed fertility interventions offered in addition to standard IVF and ICSI and recorded statements about interventions that claimed or implied improvements in fertility in healthy women. We recorded which claims were quantified, and the evidence cited in support of the claims. Two reviewers extracted data from websites. We accessed websites from 21 December 2015 to 31 March 2016. We found 233 websites for HFEA-registered fertility treatment centres, of which 152 (65%) were excluded as duplicates or satellite centres, 2 were andrology clinics and 5 were unavailable or under construction websites. In total, 74 fertility centre websites, incorporating 1401 web pages, were examined for claims. We found 276 claims of benefit relating to 41 different fertility interventions made by 60 of the 74 centres (median 3 per website; range 0 to 10). Quantification was given for 79 (29%) of the claims. 16 published references were cited 21 times on 13 of the 74 websites. Many fertility centres in the UK offer a range of treatments in addition to standard IVF procedures, and for many of these interventions claims of benefit are made. In most cases, the claims are not quantified and evidence is not cited to support the claims. There is a need for more information on interventions to be made available by fertility centres, to support well-informed treatment decisions.


Tidal forced expirations. ERS/ATS Task Force on Standards for Infant Respiratory Function Testing. European Respiratory Society/American Thoracic Society.
The progress of infant lung function testing has been retarded by both the lack of user-friendly, widely available and affordable equipment and the lack of standardized methodology. The European Respiratory Society/American Thoracic Society Task Force on Standards for Infant Respiratory Function Testing was formed in an attempt to address these deficiencies. This document represents the consensus of investigators with vast experience in the measurement of lung function in infants. The present recommendations deal with equipment requirements, study procedures and reporting of data for measurements of forced expiration at end-tidal inspiration. They represent the "state of the art" in 1999. They are not meant to inhibit further developments in this technique. The authors anticipate that these guidelines will be updated regularly as knowledge progresses.


Medical students' beliefs about nine different specialties.
A total of 449 preclinical and postclinical students from three London University medical schools completed one of nine versions of a 50 item questionnaire seeking their attitudes to nine specialties: anaesthetics, general practice, gynaecology, hospital medicine, paediatrics, pathology, psychiatry, radiology, and surgery. There were three main findings. Firstly, though item by item analysis yielded interesting and predictable differences, such as the negative attitudes to psychiatry, the students' attitudes and beliefs were multidimensional: whereas any specialty might be seen as highly positive on one dimension--for example, effectiveness--it might be seen as highly negative on another--for example, relationships with patients. Secondly, the nine specialties seemed to be discriminative on two dimensions--soft versus hard; general versus specific--such that psychiatry was seen as soft and specific, general practice soft and general, and surgery hard but neither general nor specific. Thirdly, these attitudes tended to differ between preclinical and clinical students, but only modestly, in that some extreme (positive and negative) attitudes were modified by experience.


Energy Dissipation in Monolayer MoS2 Electronics.
The advancement of nanoscale electronics has been limited by energy dissipation challenges for over a decade. Such limitations could be particularly severe for two-dimensional (2D) semiconductors integrated with flexible substrates or multilayered processors, both being critical thermal bottlenecks. To shed light into fundamental aspects of this problem, here we report the first direct measurement of spatially resolved temperature in functioning 2D monolayer MoS2 transistors. Using Raman thermometry, we simultaneously obtain temperature maps of the device channel and its substrate. This differential measurement reveals the thermal boundary conductance of the MoS2 interface with SiO2 (14 ± 4 MW m-2 K-1) is an order magnitude larger than previously thought, yet near the low end of known solid-solid interfaces. Our study also reveals unexpected insight into nonuniformities of the MoS2 transistors (small bilayer regions) which do not cause significant self-heating, suggesting that such semiconductors are less sensitive to inhomogeneity than expected. These results provide key insights into energy dissipation of 2D semiconductors and pave the way for the future design of energy-efficient 2D electronics.


What Factors are Associated With a Surgical Site Infection After Operative Treatment of an Elbow Fracture?
Surgical site infections are one of the more common major complications of elbow fracture surgery and can contribute to other adverse outcomes, prolonged hospital stays, and increased healthcare costs. We asked: (1) What are the factors associated with a surgical site infection after elbow fracture surgery? (2) When taking the subset of closed elbow fractures only, what are the factors associated with a surgical site infection? (3) What are the common organisms isolated from an elbow infection after open treatment? One thousand three hundred twenty adult patients underwent surgery for an elbow fracture between January 2002 and July 2014 and were included in our study. Forty-eight of 1320 patients (4%) had a surgical site infection develop. Thirty-four of 1113 patients with a closed fracture (3%) had a surgical site infection develop. For all elbow fractures, use of plate and screw fixation (adjusted odds ratio [OR]= 2.2; 95% CI, 1.0-4.5; p = 0.041) and use of external fixation before surgery (adjusted OR = 4.7; 95% CI, 1.1-21; p = 0.035) were associated with higher infection rates. When subset analysis was performed for closed fractures, only smoking (adjusted OR = 2.2; 95% CI, 1.1-4.5; p = 0.023) was associated with higher infection rates. Staphylococcus aureus was the most common bacteria cultured (59%). The only modifiable risk factor for a surgical site infection after open reduction and internal fixation was cigarette smoking. Plate fixation and temporary external fixation are likely surrogates for more complex injuries, therefore no recommendations should be inferred from this association. Surgeons should counsel patients who smoke. Level IV, prognostic study.


Membrane type-1-matrix metalloproteinase expressed by prostate carcinoma cells cleaves human laminin-5 beta3 chain and induces cell migration.
Degradation of the extracellular matrix by proteolytic enzymes is a central aspect of physiological and pathologic tissue-remodeling processes such as trophoblastic implantation, wound healing, and tumor invasion. We have hypothesized that prostate adenocarcinoma cell invasion through the normal basal lamina is attributable in part to metalloproteinase-induced cleavage of laminin-5 (Ln-5) and enhanced motility of the cancer cells. We studied the role of membrane type-1-matrix metalloproteinase (MT1-MMP) expressed on the surface of prostate tumor cells in cleaving Ln-5 and enhancing the migration of prostate tumor cells. We also determined the nature of the MT1-MMP cleavage of human Ln-5 and how this altered Ln-5 changes the migration of prostate carcinoma cells. We found that human MT1-MMP cleaves purified human Ln-5 to an 80-kDa fragment. Mass spectrometry analyses of the 80-kDa cleaved product by trypsin and chymotrypsin gave 14 and 9 different peptide sequences, respectively, that were identical to the expected amino acid sequence of the Ln-5-beta3 chain. The recovered peptides represent 14.4% (trypsin) and 10.3% (chymotrypsin) of Ln-5-beta3 chain by amino acid count. Both trypsin and chymotrypsin digestion of MT1-MMP-cleaved product of Ln-5 did not show any other peptides that were identical to the other chains of Ln-5. Using a linear migration assay we found that the Ln-5 cleaved by MT1-MMP enhanced the migration of DU-145 prostate carcinoma cells by 2-fold compared with uncleaved Ln-5. The use of blocked antisense MT1-MMP oligonucleotides inhibited the migration of DU-145 cells on Ln-5. We also found that the prostate carcinoma cells expressing high levels of MT1-MMP, such as PC3N and PPC, demonstrated enhanced migration on human Ln-5-coated substrate, and this migration was inhibited using blocked antisense MT1-MMP oligonucleotides. In conclusion, this is a novel and important finding where we have shown that beta3-chain is cleaved by MT1-MMP, and this cleavage enhances migration of prostate cancer cells.


Homogenous distribution of fast response action potentials in canine pulmonary vein sleeves: a contradictory report.
Pulmonary veins may serve as source of ectopic focus (or foci) in initiating atrial tachyarrhythmias in human beings. However, the animal model for such focal atrial fibrillation is still lacking and cellular mechanism for arrhythmias remains to be studied. Recently, a series of reports of cellular electrophysiological characterization of pulmonary vein sleeves demonstrated an extremely high incidence of automaticity (varied from 40 to 76%) and triggered activity (from 0 to 44%) in normal healthy control dogs and rabbits. The present study was therefore designed to re-investigate the cellular electrophysiological properties of canine pulmonary veins. Intracellular action potentials were characterized in pulmonary vein sleeves in 50 normal healthy dogs. Conventional glass microelectrode recording technique was used. Experiments were focused on the incidence of automaticity and triggered activity in pulmonary vein sleeve tissues. Surprisingly, our results showed that all pulmonary vein sleeves tissues in these dogs displayed fast-response action potentials under the well-controlled experimental condition (100%, n=50). No spontaneous pacemaking activities, early or delayed afterdepolarisations were observed (0%, n=50). No high-frequency spikes or irregular rhythm could be recorded in all experiments (0%, n=50). Both the frequency response and membrane responsiveness of the pulmonary vein action potentials were characterized. No electrophysiological inhomogeneity between the distal and the proximal part of the sleeves was observed. In conclusion, canine pulmonary vein sleeves do not display arrhythmogenic activities under normal physiological conditions. The possible explanations for the controversy in pulmonary veins electrophysiology were discussed.


Crystal structure of a type III pantothenate kinase: insight into the mechanism of an essential coenzyme A biosynthetic enzyme universally distributed in bacteria.
Pantothenate kinase (PanK) catalyzes the first step in the five-step universal pathway of coenzyme A (CoA) biosynthesis, a key transformation that generally also regulates the intracellular concentration of CoA through feedback inhibition. A novel PanK protein encoded by the gene coaX was recently identified that is distinct from the previously characterized type I PanK (exemplified by the Escherichia coli coaA-encoded PanK protein) and type II eukaryotic PanKs and is not inhibited by CoA or its thioesters. This type III PanK, or PanK-III, is widely distributed in the bacterial kingdom and accounts for the only known PanK in many pathogenic species, such as Helicobacter pylori, Bordetella pertussis, and Pseudomonas aeruginosa. Here we report the first crystal structure of a type III PanK, the enzyme from Thermotoga maritima (PanK(Tm)), solved at 2.0-A resolution. The structure of PanK(Tm) reveals that type III PanKs belong to the acetate and sugar kinase/heat shock protein 70/actin (ASKHA) protein superfamily and that they retain the highly conserved active site motifs common to all members of this superfamily. Comparative structural analysis of the PanK(Tm) active site configuration and mutagenesis of three highly conserved active site aspartates identify these residues as critical for PanK-III catalysis. Furthermore, the analysis also provides an explanation for the lack of CoA feedback inhibition by the enzyme. Since PanK-III adopts a different structural fold from that of the E. coli PanK -- which is a member of the "P-loop kinase"superfamily -- this finding represents yet another example of convergent evolution of the same biological function from a different protein ancestor.


Regeneration and repair in multiple sclerosis: the role of cell transplantation.
Physiological (spontaneous) and reactive (reparative) regenerative processes are fundamental part of life and greatly differ among the different animals and tissues. While spontaneous regeneration naturally occurs upon cell attrition, reparative regeneration occurs as a consequence of tissue damage. Both spontaneous and reparative regeneration play an important role in maintaining the normal equilibrium of the central nervous system (CNS) as well as in promoting its repair upon injury. Cells play a critical role in reparative regeneration as regenerating structures (cells or tissues) depend on the proliferation without (de)differentiation of parenchymal cells surviving to the injury, proliferation of stem (progenitor) cells resident in the injured tissue, dedifferentiation of mature cells in the remaining tissue, or by the influx of stem cells originating outside the damaged tissue. Considering the central role of stem and progenitor cells in regeneration, a spur of experimental stem cell-based transplantation approaches for tissue (e.g. CNS) repair has been recently generated. This review will focus on the therapeutic efficacy of different sources of somatic stem cells - and in particular on those of neural origin - in promoting CNS repair in a chronic (auto)immune-mediated inflammatory disorder such as multiple sclerosis.


Distribution of open reading frames of plasticity region of strain J99 in Helicobacter pylori strains isolated from gastric carcinoma and gastritis patients in Costa Rica.
The plasticity region of Helicobacter pylori strain J99 is a large chromosomal segment containing 33 strain-specific open reading frames (ORFs) with characteristics of a pathogenicity island. To study the diversity of the plasticity region, 22 probes corresponding to 20 ORFs inside the plasticity region and two ORFs on its boundaries were hybridized to genomic DNA isolated from clinical strains of H. pylori from patients with gastritis or gastric adenocarcinoma. Highly variable hybridization patterns were observed. The majority of the clinical strains presented a hybridization profile similar to that of J99; thus, these ORFs are not J99 strain specific. No association was found between a particular hybridization pattern and the clinical origin of the strain. Nevertheless, two single ORFs (JHP940 and JHP947) were more likely to be found in gastric cancer strains. They may be new pathogenicity markers. An in vitro expression study of these ORFs was also performed for the J99 strain, under different conditions. Thirteen ORFs were consistently expressed, six were consistently shut off, and three were expressed differentially. Most of the constitutionally expressed genes were located on the 3' part of the plasticity region. Our results show that the plasticity region, rather than being considered a pathogenicity island per se, should be considered a genomic island, which represents a large fragment of foreign DNA integrated into the genome and not necessarily implicated in the pathogenic capacity of the strain.


The effect of dye coverage on the performance of dye-sensitized solar cells with a cobalt-based electrolyte.
The effect of dye coverage of the mesoporous TiO2 electrode on the performance of dye-sensitized solar cells based on the cobalt tris(bipyridine) electrolyte and the D35 dye was studied in detail. The dye coverage was controlled by using a dye bath with different dye concentrations and containing an inert salt, LiClO4, which was found to promote equilibrium conditions in the dye adsorption process. The amount of adsorbed D35 dye on mesoporous TiO2 was reasonably fit using the Langmuir adsorption isotherm, with a binding constant of 55 000 M(-1). Upon increasing the dye coverage on the TiO2 electrode, the electron lifetime in the dye-sensitized solar cell increased remarkably, demonstrating the blocking behavior of the D35 dye at the TiO2-electrolyte interface. Consequently, the solar cell efficiency increased dramatically with the D35 dye coverage.


A model of empathic communication in the medical interview.
To formulate an empirically derived model of empathic communication in medical interviews by describing the specific behaviors and patterns of interaction associated with verbal expressions of emotion. A descriptive, qualitative study of verbal exchanges using 11 transcripts and 12 videotapes of primary care office visits to a total of 21 physicians. An urban health maintenence organization (HMO), an urban university-based general medicine clinic, and an urban community hospital general medicine clinic. ANALYTIC METHOD: Individual review of transcripts by each research team member to identify instances of expressed or implied emotional themes and to observe the physicians' responses. Individual ratings were compared in group discussions to achieve consensus about the classifications. Similar consensus-based classification was used for review of videotapes. We observed that patients seldom verbalize their emotions directly and spontaneously, tending to offer clues instead. If invited to elaborate, patients may then express the emotional concern directly, and the physician may respond with an accurate and explicit acknowledgment. In most of the interviews, the physicians allowed both clues and direct expressions of affect to pass without acknowledgment, returning instead to the preceding topic, usually the diagnostic exploration of symptoms. With emotional expression so terminated, some patients attempted to raise the topic again, sometimes repeatedly and with escalating intensity. We noted a parallel dynamic for encounters in which patients sought praise. We summarized the full interactional sequence in a simple descriptive model. This empirically derived model of empathic communication has practical implications for clinicians and students who want to improve their communication and relationship skills. Based on our observations, the basic empathic skills seem to be recognizing when emotions may be present but not directly expressed, inviting exploration of these unexpressed feelings, and effectively acknowledging these feelings so the patient feels understood. The frequent lack of acknowledgment by physicians of both direct and indirect expressions of affect poses a threat to the patient-physician relationship and warrants further study.


Choline supplementation and DNA methylation in the hippocampus and prefrontal cortex of rats exposed to alcohol during development.
Some of the most frequent deficits seen in children with fetal alcohol spectrum disorders (FASD) and in animal models of FASD are spatial memory impairments and impaired executive functioning, which are likely related to alcohol-induced alterations of the hippocampus and prefrontal cortex (PFC), respectively. Choline, a nutrient supplement, has been shown in a rat model to ameliorate some of alcohol's teratogenic effects, and this effect may be mediated through choline's effects on DNA methylation. Alcohol was given by intragastric intubation to rat pups during the neonatal period (postnatal days 2 to 10) (ET group), which is equivalent to the third trimester in humans and a period of heightened vulnerability of the brain to alcohol exposure. Control groups included an intubated control group given the intubation procedure without alcohol (IC) and a nontreated control group (NC). Choline or saline was administered subcutaneously to each subject from postnatal days 2 to 20. On postnatal day 21, the brains of the subjects were removed and assayed for global DNA methylation patterning as measured by chemiluminescence using the cpGlobal assay in both the hippocampal region and PFC. Alcohol exposure caused hypermethylation in the hippocampus and PFC, which was significantly reduced after choline supplementation. In contrast, control animals showed increases in DNA methylation in both regions after choline supplementation, suggesting that choline supplementation has different effects depending upon the initial state of the brain. This study is the first to show changes in global DNA methylation of the hippocampal region and PFC after neonatal alcohol exposure. Choline supplementation impacts global DNA methylation in these 2 brain regions in alcohol-exposed and control animals in a differential manner. The current findings suggest that both alcohol and choline have substantial impact on the epigenome in the PFC and hippocampus, and future studies will be needed to describe which gene families are impacted in such a way that function of the nervous system is changed.


A group analysis using the Multiregression Dynamic Models for fMRI networked time series.
Connectivity studies of the brain are usually based on functional Magnetic Resonance Imaging (fMRI) experiments involving many subjects. These studies need to take into account not only the interaction between areas of a single brain but also the differences amongst those subjects. In this paper we develop a methodology called the group-structure (GS) approach that models possible heterogeneity between subjects and searches for distinct homogeneous sub-groups according to some measure that reflects the connectivity maps. We suggest a GS method that uses a novel distance based on a model selection measure, the Bayes factor. We then develop a new class of Multiregression Dynamic Models to estimate individual networks whilst acknowledging a GS type dependence structure across subjects. We compare the efficacy of this methodology to three other methods, virtual-typical-subject (VTS), individual-structure (IS) and common-structure (CS), used to infer a group network using both synthetic and real fMRI data. We find that the GS approach provides results that are both more consistent with the data and more flexible in their interpretative power than its competitors. In addition, we present two methods, the Individual Estimation of Multiple Networks (IEMN) and the Marginal Estimation of Multiple Networks (MEMN), generated from the GS approach and used to estimate all types of networks informed by an experiment -individual, homogeneous subgroups and group networks. These methods are then compared both from a theoretical perspective and in practice using real fMRI data.


Antihypertensive Treatment in Severe Aortic Stenosis.
Previously, antihypertensive treatment in severe aortic stenosis was considered a relative contraindication. However, recent studies have shown that antihypertensive treatment may be safe and even beneficial in terms of reducing the progression of left ventricular pressure overload and even retarding the progression of valvular aortic stenosis. To date, no randomized clinical trials have been performed and no definite treatment guideline exist for the proper antihypertensive regimens. Antihypertensive treatment with β-blockers has generally been avoided in patients with severe aortic stenosis (AS) due to the concerns for inducing left ventricular dysfunction and hemodynamic compromise in the presence of severe outflow tract obstruction. Although it remains unclear whether antihypertensive treatment with a β-blocker is associated with increased risk of cardiovascular events in patients with AS, recent studies have shown that the use of β-blockers may be safe and may even be beneficial. Renin-angiotensin system (RAS) are upregulated in AS and have been shown to be involved in valve calcification and progression in both experimental models and in human trials. As such, theoretically, RAS inhibition would have benefit in retarding the progression of valvular stenosis as well as have benefit in left ventricle remodeling. Recent clinical studies are indeed showing that use of RAS inhibition may be beneficial in patients with AS. Future clinical trials to establish the ideal target blood pressure and antihypertensive regimens in severe AS is essential.


A method to predict and understand fish survival under dynamic chemical stress using standard ecotoxicity data.
The authors present a method to predict fish survival under exposure to fluctuating concentrations and repeated pulses of a chemical stressor. The method is based on toxicokinetic-toxicodynamic modeling using the general unified threshold model of survival (GUTS) and calibrated using raw data from standard fish acute toxicity tests. The model was validated by predicting fry survival in a fish early life stage test. Application of the model was demonstrated by using Forum for Co-ordination of Pesticide Fate Models and Their Use surface water (FOCUS-SW) exposure patterns as model input and predicting the survival of fish over 485 d. Exposure patterns were also multiplied by factors of five and 10 to achieve higher exposure concentrations for fish survival predictions. Furthermore, the authors quantified how far the exposure profiles were below the onset of mortality by finding the corresponding exposure multiplication factor for each scenario. The authors calculated organism recovery times as additional characteristic of toxicity as well as number of peaks, interval length between peaks, and mean duration as additional characteristics of the exposure pattern. The authors also calculated which of the exposure patterns had the smallest and largest inherent potential toxicity. Sensitivity of the model to parameter changes depends on the exposure pattern and differs between GUTS individual tolerance and GUTS stochastic death. Possible uses of the additional information gained from modeling to inform risk assessment are discussed.


Impacting child health outcomes in congenital heart disease: Cluster randomized controlled trial protocol of in-clinic physical activity counselling.
Most (>90%) children with congenital health defects are not active enough for optimal health. Proactively promoting physical activity during every clinic visit is recommended, but rarely implemented due to a lack of appropriate resources. This cluster randomized controlled trial will implement an evidence-based, multi-faceted physical activity intervention. All eligible patients at small (London, ON), medium (Ottawa, ON) and large (Edmonton, AB) pediatric cardiac clinics will be approached, with randomization to intervention/control by clinic and week. Intervention patients will be counselled with 5 key physical activity messages, have questions about physical activity answered, and have access to a custom web site with personalized activity suggestions and support from a Registered Kinesiologist. The primary outcome is daily physical activity (number of steps, minutes of moderate-to-vigorous activity) assessed via pedometer one week per month for 6-months. Standardized questionnaires assess activity motivation and quality of life at baseline and end of study. Healthcare outcomes will be clinic visit time and contacts for physical activity concerns. Repeated measures ANCOVA will compare control/intervention pedometer outcomes, adjusting for covariates (alpha=0.05). This trial aims to determine whether providing resources and protocols enables clinicians to counsel about physical activity as part of every pediatric cardiology appointment. Evaluations of healthcare system impact and intervention delivery in small, medium and large clinics will assess applicability for implementation in all pediatric cardiac clinics. The impact on physical activity motivation and participation will evaluate the effectiveness of this standardized approach for increasing physical activity in children with congenital heart defects.


Acute Regression in Down Syndrome.
Acute regression has been reported in some individuals with Down syndrome (DS), typically occurring between the teenage years and mid to late 20s. Characterized by sudden, and often unexplained, reductions in language skills, functional living skills and reduced psychomotor activity, some individuals have been incorrectly diagnosed with Alzheimer's disease (AD). This paper compares five individuals with DS who previously experienced acute regression with a matched group of 15 unaffected individuals with DS using a set of AD biomarkers. While the sample was too small to conduct statistical analyses, findings suggest there are possible meaningful differences between the groups on proteomics biomarkers (e.g., NfL, total tau). Hippocampal, caudate and putamen volumes were slightly larger in the regression group, the opposite of what was hypothesized. A slightly lower amyloid load was found on the PET scans for the regression group, but no differences were noted on tau PET. Some proteomics biomarker findings suggest that individuals with DS who experience acute regression may be at increased risk for AD at an earlier age in comparison to unaffected adults with DS. However, due to the age of the group (mean 38 years), it may be too early to observe meaningful group differences on image-based biomarkers.


Health related quality of life in Friedreich Ataxia in a large heterogeneous cohort.
This study assessed the Health Related Quality of Life (HRQOL) of individuals with Friedreich Ataxia (FRDA) through responses to HRQOL questionnaires. The SF-36, a generic HRQOL instrument, and symptom specific scales examining vision, fatigue, pain and bladder function were administered to individuals with FRDA and analyzed by comparison with disease features. Multiple linear regression models were used to study independent effects of genetic severity and age. Assessments were performed at baseline then intermittently after that. Subjects were on average young adults. For the SF36, the subscale with the lowest HRQOL score was the physical function scale, while the emotional well-being score was the highest. The physical function scale correlated with age of onset, duration, and subject age. In assessment of symptom specific scales, bladder control scores (BLCS) correlated with duration and age, while impact of visual impairment scores (IVIS) correlated with duration. In linear regression models, the BLCS, Pain Effect Score, and IVIS scores were predicted by age and GAA length; modified fatigue impact scale scores were predicted only by GAA length. Physical function and role limitation scores declined over time. No change was seen over time in other SF-36 subscores. Symptom specific scales also worsened over time, most notably the IVIS and BLCS. The SF-36 and symptom specific scales capture dysfunction in FRDA in a manner that reflects disease status. HRQOL dysfunction was greatest on physically related scales; such scales correlated with disease duration, indicating that they worsen with progressing disease.


Strong spin frustration and negative magnetization in LnCu3(OH)6Cl3 (Ln = Nd and Sm) with triangular lattices: the effects of lanthanides.
Herbertsmithite- and kapellasite-type compounds with triangular lattices (i.e. Kagomé) as the most promising candidates for realizing the exotic quantum spin liquid (QSL) state have recently attracted significant attention in condensed matter physics and materials science but are often adversely affected by dimensional imperfections arising from significant cation mixing. Also, interaction mechanisms between the Kagomé lattices and ionic impurities remain unclear. Herein we report on the synthesis, crystal structures and magnetic properties of a new class of kapellasite-type compounds LnCu3(OH)6Cl3 (Ln = Nd and Sm) with two overlapped triangular lattices. These compounds are characterized by the triangular lattices of Cu2+ superimposed by another triangular lattice of paramagnetic Ln3+. The magnetic properties of LnCu3(OH)6Cl3 feature strong spin frustrations as well as antisymmetrical Dzyaloshinskii-Moriya interactions resulting in canted antiferromagnetic ordering with the Néel temperature (TN) of ∼20 K and ∼18 K for NdCu3(OH)6Cl3 and SmCu3(OH)6Cl3, respectively. Moreover, negative magnetization at low temperatures was firstly observed in Kagomé lattice compounds, arising from geometrical spin frustration and competing interactions within two overlapped triangular lattices.


Access to parks and physical activity: an eight country comparison.
Several systematic reviews have reported mixed associations between access to parks and physical activity, and suggest that this is due to inconsistencies in the study methods or differences across countries. An international study using consistent methods is needed to investigate the association between access to parks and physical activity. The International Physical Activity and Environment Network (IPEN) Adult Study is a multi-country cross-sectional study using a common design and consistent methods. Accelerometer, survey and Geographic Information Systems (GIS) data for 6,181 participants from 12 cities in 8 countries (Belgium, Brazil, Czech Republic, Denmark, Mexico, New Zealand, UK, USA) were used to estimate the strength and shape of associations of 11 measures of park access (1 perceived and 10 GIS-based measures) with accelerometer-based moderate-to-vigorous physical activity (MVPA) and four types of self-reported leisure-time physical activity. Associations were estimated using generalized additive mixed models. More parks within 1 km from participants' homes were associated with greater leisure-time physical activity and accelerometer-measured MVPA. Respondents who lived in the neighborhoods with the most parks did on average 24 minutes more MVPA per week than those living in the neighborhoods with the lowest number of parks. Perceived proximity to a park was positively associated with multiple leisure-time physical activity outcomes. Associations were homogeneous across all cities studied. Living in neighborhoods with many parks could contribute with up to 1/6 of the recommended weekly Having multiple parks nearby was the strongest positive correlate of PA. To increase comparability and validity of park access measures, we recommend that researchers, planners and policy makers use the number of parks within 1 km travel distance of homes as an objective indicator for park access in relation to physical activity.


Public health efforts to build a surveillance system for child maltreatment mortality: lessons learned for stakeholder engagement.
Reducing the number of largely preventable and tragic deaths due to child maltreatment (CM) requires an understanding of the magnitude of and risk factors for fatal CM and targeted research, policy, and prevention efforts. Public health surveillance offers an opportunity to improve our understanding of the problem of CM. In 2006, the Centers for Disease Control and Prevention (CDC) funded state public health agencies in California, Michigan, and Oregon to implement a model approach for routine and sustainable CM surveillance and evaluated the experience of those efforts. We describe the experiences of 3 state health agencies in building collaborations and partnerships with multiple stakeholders for CM surveillance. Qualitative, structured key informant interviews were carried out during site visits as part of an evaluation of a CDC-funded project to implement a model approach to CM surveillance. Key informants included system stakeholders from state health agencies, law enforcement, child protective services, the medical community, and child welfare advocacy groups in the 3 funded states. Factors that facilitated stakeholder engagement for CM surveillance included the following: streamlining and coordinating the work of Child Death Review Teams (CDRTs); demonstrating the value of surveillance to non-public health partners; codifying relationships with participating agencies; and securing the commitment of decision-makers. Legislative mandates were helpful in bringing key stakeholders together, but it was not sufficient to ensure sustained engagement. The engagement process yielded multiple benefits for the stakeholders including a deeper appreciation of the complexity of defining CM; a greater understanding of risk factors for CM; and enhanced guidance for prevention and control efforts. States considering or currently undertaking CM surveillance can glean useful insights from the experiences of these 3 states and apply them to their own efforts to engage stakeholders.


Synthetic aperture radar image correlation by use of preprocessing for enhancement of scattering centers.
We demonstrate that a significant improvement can be obtained in the recognition of complicated synthetic aperture radar images taken from the Moving and Stationary Target Acquisitions and Recognition database. These images typically have a low number of scattering centers and high noise. We first preprocess the images and the templates formed from them so that their scattering centers are enhanced. Our technique can produce high-quality performance in several correlation criteria. For realistic automatic target recognition systems, our approach should make it easy to implement optical recognition systems with binarized data for many different types of correlation filter and should have a great effect on feeding data-compressed (binarized) information into either digital or optical processors.


Functional characterisation of glucose transport in bovine articular chondrocytes.
The adequate provision of glucose to articular chondrocytes is essential to sustain their predominantly anaerobic metabolism; glucose is also a precursor for the extracellular matrix macromolecules which these cells synthesise. Impaired glucose uptake would compromise cell function and potentially result in an imbalance of matrix synthesis and degradation, leading to osteoarthritis. We studied the glucose influx pathway into bovine articular chondrocytes using 2-deoxy- d-[(3)H]-glucose (DOG). Uptake occurs via an extracellular pH (pH(o))-insensitive, phloretin- and cytochalasin B-sensitive pathway, hallmarks of the GLUT family of facilitative glucose transporters, with a K(m) of 0.35+/-0.11 mM. Uptake was affected by a number of physiologically relevant factors: (1) raised hydrostatic pressure (1-30 MPa) inhibited DOG uptake by up to 30%; (2) interleukin-1 (IL-1beta) reduced uptake via an increase in transporter affinity; (3) glucosamine inhibited glucose uptake in a manner consistent with the actions of a competitive inhibitor. Given the involvement of IL-1beta in osteoarthritis and the protective role assigned to glucosamine, these findings implicate an important role for glucose delivery in chondrocyte energy production and matrix metabolism, which, therefore, may potentially affect the maintenance of cartilage integrity.


Bio++: efficient extensible libraries and tools for computational molecular evolution.
Efficient algorithms and programs for the analysis of the ever-growing amount of biological sequence data are strongly needed in the genomics era. The pace at which new data and methodologies are generated calls for the use of pre-existing, optimized-yet extensible-code, typically distributed as libraries or packages. This motivated the Bio++ project, aiming at developing a set of C++ libraries for sequence analysis, phylogenetics, population genetics, and molecular evolution. The main attractiveness of Bio++ is the extensibility and reusability of its components through its object-oriented design, without compromising the computer-efficiency of the underlying methods. We present here the second major release of the libraries, which provides an extended set of classes and methods. These extensions notably provide built-in access to sequence databases and new data structures for handling and manipulating sequences from the omics era, such as multiple genome alignments and sequencing reads libraries. More complex models of sequence evolution, such as mixture models and generic n-tuples alphabets, are also included.


Delayed anaphylaxis to red meat in patients with IgE specific for galactose alpha-1,3-galactose (alpha-gal).
Anaphylaxis is a severe allergic reaction that can be rapidly progressing and fatal. In instances where the triggering allergen is not known, establishing the etiology of anaphylaxis is pivotal to long-term risk management. Our recent work has identified a novel IgE antibody (Ab) response to a mammalian oligosaccharide epitope, galactose-alpha-1,3-galactose (alpha-gal), that has been associated with two distinct forms of anaphylaxis: (1) immediate onset anaphylaxis during first exposure to intravenous cetuximab, and (2) delayed onset anaphylaxis 3-6 h after ingestion of mammalian food products (e.g., beef and pork). The results of our studies strongly suggest that tick bites are a cause, if not the only significant cause, of IgE Ab responses to alpha-gal in the southern, eastern and central United States. Patients with IgE Ab to alpha-gal continue to emerge and, increasingly, these cases involve children. This IgE Ab response cross-reacts with cat and dog but does not appear to pose a risk for asthma; however, it may impair diagnostic testing in some situations.


A biochemical and histopathological evaluation of generalized pulp calcification in young permanent teeth.
Pulp calcifications are a frequent finding on bitewing and periapical radiographs in older age-groups but their occurrence in the entire dentition in young subjects is unusual. We report such an unusual occurrence of generalized pulp calcification in a 13-year-old Indian female. Radiographic examination of the dentition revealed pulp calcifications in all permanent teeth, located mostly in the pulp chamber but with some in the root canals. The patient's dental, medical, and family history was noncontributory. Biochemical analysis of the removed pulp calcification from one of the teeth during endodontic treatment showed large amounts of calcium, phosphorus, and carbonate. However, metabolic evaluation of patient through liver and kidney function tests and other blood investigations did not reveal any metabolic disorder. The patient was also evaluated for any systemic, syndromic, or genetic involvement but this was also noncontributory. Therefore, we propose that this unusual case of generalized pulp calcification is of idiopathic origin. In this work, histopathological and biochemical evaluations of the pulp calcification was done to try and understand the initiation and progress of calcifications in pulpal tissue.


Validation of peptide epitope microarray experiments and extraction of quality data.
Within the last decade, the development of antigen microarray slides has enabled the simultaneous measurement of serum reactivity to hundreds of peptides in a single biological sample. Despite this considerable scientific progress, many issues remain regarding the quality, analysis and interpretation of the data these slides produce. There is currently no accepted approach to guide data analysis, and researchers use a wide variety of statistical methods and software tools. We designed and implemented a laboratory experiment to assess the reliability and range of measurement of peptide microarray data, and present graphical and statistical procedures for pre-processing so that quality data can be extracted for addressing biological hypotheses. Synthetic peptides spanning the proteins Ag85A, Ag85B, CFP10, MPT51/MPB51, TB10.4 and ESAT-6 were chosen as a paradigm to screen for serum reactivity to Mycobacteria tuberculosis (MTB). We explored various quantitative and graphical methods for presenting the responses from a slide. We replicated assays of samples from five TB-positive individuals to examine reproducibility, and used linear mixed models to investigate the various sources of variability, and to assess the range of measurement. We use our methods to extract data from the five TB-positive individuals and five healthy controls, and analyse the "normalized" responses using the freely available SAM package. The ratio of foreground to background signal (on a log scale) provides an appropriate response index. A two-dimensional graphical display clearly illustrates the responses from the control and peptide features on a slide. Mixed model analysis of the replicated slides found a high reproducibility of the assay between operators, days and experiments. The range of measurement was also satisfactory. Our analysis of the normalized responses from the five TB-positive patients and five healthy controls suggested that 10 of the 363 peptides assessed had significantly higher responses in the TB-positive group. Carefully designed laboratory experiments and rigorous statistical analysis can enable the removal of technical artefacts to produce quality peptide array data for addressing biological hypotheses. These instruments, which enable valid comparisons across slides and/or batches of slides, will escort future comparative analyses targeting high content serum reactivity profiling against a broad array of B-cell epitopes.


Uniform binding of aminoacyl-tRNAs to elongation factor Tu by thermodynamic compensation.
Elongation factor Tu (EF-Tu) binds all elongator aminoacyl-transfer RNAs (aa-tRNAs) for delivery to the ribosome during protein synthesis. Here, we show that EF-Tu binds misacylated tRNAs over a much wider range of affinities than it binds the corresponding correctly acylated tRNAs, suggesting that the protein exhibits considerable specificity for both the amino acid side chain and the tRNA body. The thermodynamic contributions of the amino acid and the tRNA body to the overall binding affinity are independent of each other and compensate for one another when the tRNAs are correctly acylated. Because certain misacylated tRNAs bind EF-Tu significantly more strongly or weakly than cognate aa-tRNAs, EF-Tu may contribute to translational accuracy.


Connection routing for microoptic systems.
A recognized model for an all-optical digital computer consists of arrays of optical logic devices interconnected in free space with bulk optical components. A problem with this approach is that device arrays must be spaced to allow for components placed between them such as lenses, gratings, and beam splitters. The latency introduced by this spacing may be greater than device switching times, which means that tight loop processing of digital information is not possible. A solution to this problem is to replace large optical components with monolithically fabricated devices, lenses, mirrors, beam splitters, and combiners. Some connection freedom is lost due to practical limits on configurations of small components. These limits and a method to minimize their effects are explored here. It is concluded that log(2)N optical interconnects such as perfect shuffles and crossovers are not necessary for efficient digital architectures and that simple split, shift, and combine operations may be preferred for simpler optical implementations.


Chromosomes move poleward in anaphase along stationary microtubules that coordinately disassemble from their kinetochore ends.
During the movement of chromosomes in anaphase, microtubules that extend between the kinetochores and the poles shorten. We sought to determine where subunits are lost from these microtubules during their shortening. Prophase or prometaphase cells on coverslips were injected with fluoresceinated tubulin and allowed to progress through mitosis. Immediately after the onset of anaphase, a bar-shaped beam of laser light was used to mark a domain on the kinetochore fibers by photobleaching a band, approximately 1.0 micron wide, across the spindle. In different cells, spindles were photobleached at varying distances from the chromosomes. Cells were allowed to continue in anaphase until the chromosomes had further separated. They were then lysed, fixed, and prepared for double-label immunofluorescence with an antibody to fluorescein that does not bind appreciably to bleached fluorescein, and with an antibody to tubulin. Photobleached domains of microtubules appeared as bands of reduced fluorescence in the anti-fluorescein image. However, the anti-tubulin labeling revealed that microtubules were present and continuous through the photobleached domains. In all cases, the chromosomes approached and invaded the bleached domain while the bleached domain itself remained stationary with respect to the near pole. These results demonstrate that the chromosomes move along stationary kinetochore microtubules and that depolymerization of these microtubules during anaphase takes place at the kinetochore. In contrast to the generally accepted older view that chromosomes are passive objects pulled by "traction fibers," we suggest that the kinetochore is an active participant in generating the motive force that propels the chromosome to the pole.


Fluorescent 1,4-Naphthoquinones To Visualize Diffuse and Dense-Core Amyloid Plaques in APP/PS1 Transgenic Mouse Brains.
Recent clinical approvals of brain imaging radiotracers targeting amyloid-β provided clinicians the tools to detect and confirm Alzheimer's disease pathology without autopsy or biopsy. While current imaging agents are effective in postsymptomatic Alzheimer's patients, there is much room for improvement in earlier diagnosis, hence prompting a need for new and improved amyloid imaging agents. Here we synthesized 41 novel 1,4-naphthoquinone derivatives and initially discovered 14 antiamyloidogenic compounds via in vitro amyloid-β aggregation assay; however, qualitative analyses of these compounds produced conflicting results and required further investigation. Follow-up docking and biophysical studies revealed that four of these compounds penetrate the blood-brain barrier, directly bind to amyloid-β aggregates, and enhance fluorescence properties upon interaction. These compounds specifically stain both diffuse and dense-core amyloid-β plaques in brain sections of APP/PS1 double transgenic Alzheimer's mouse models. Our findings suggest 1,4-naphthoquinones as a new scaffold for amyloid-β imaging agents for early stage Alzheimer's.


NTP Toxicology and Carcinogenesis Studies of Dimethyl Hydrogen Phosphite (CAS No. 868-85-9) in F344/N Rats and B6C3F1 Mice (Gavage Studies).
Dimethyl hydrogen phosphite (DMHP) is used as an intermediate in the production of insecticides and herbicides, as an additive to lubricants, and as a stabilizer in oil and plaster and was considered for use as a chemical to simulate the physical (but not the biologic) properties of anticholinesterase agents. Results of 13-week gavage studies in F344/N rats (0-400 mg DMHP/kg body weight) and in B6C3F1 mice (0-1,500 mg DMHP/kg body weight) were used to identify short-term toxicity and to establish doses for the 2-year toxicology and carcinogenesis studies. In these studies, dimethyl hydrogen phosphite (greater than 97% pure) was administered for 103 weeks in corn oil by gavage to groups of 50 male F344/N rats and to groups of 50 male and female B6C3F1 mice at doses of 0, 100, or 200 mg/kg and to groups of 50 female F344/N rats at doses of 0, 50, or 100 mg/kg. In the 2-year studies, survival of high dose male rats and high dose male mice was lower (P<0.05) than that of the vehicle controls (male rats: vehicle control, 39/50; low dose, 29/50; high dose, 23/50; male mice: 42/50; 34/50; 32/50). At the end of the studies, mean body weights were lower than those of the corresponding vehicle controls for high dose male rats (-15%), for high dose female rats (-5%), and for high dose male mice (-5%). Dimethyl hydrogen phosphite caused dose-related increases in nonneoplastic and neoplastic lesions of the lung in male and female rats. In high dose male rats, there were increased incidences of lung neoplasms, including squamous cell carcinomas (0/50; 0/50; 5/50), alveolar/bronchiolar adenomas (0/50; 0/50; 5/50), and alveolar/bronchiolar carcinomas (0/50; 1/50; 20/50). In high dose female rats, there was a marginal increase in the incidence of alveolar/bronchiolar carcinomas of the lung (0/50; 1/49; 3/50). Hyperplasia of the lung and chronic interstitial pneumonia were increased in dosed male rats and in high dose female rats. Dimethyl hydrogen phosphite caused increases in forestomach lesions in male and female rats. In male rats, there was an increased incidence of forestomach neoplasms, including squamous cell papillomas (0/50; 1/50; 3/50) and squamous cell carcinomas (0/50; 0/50; 3/50). High dose male rats had increased incidences of hyperkeratosis and hyperplasia of the forestomach. In high dose female rats, the incidence of forestomach hyperplasia was increased. Neoplastic lesions of the forestomach (a squamous cell papilloma and a squamous cell carcinoma) were found in two high dose female rats. Mineralization of the cerebellum was seen in high dose male rats (12/49) and in no other group. Focal calcification of the testis occurred at increased incidence in dosed male mice in the 2-year studies (2/50; 9/47; 24/50). Compound-related testicular atrophy was seen in male mice in the 13-week study. Dimethyl hydrogen phosphite did not induce any neoplasms in male or female mice. Dimethyl hydrogen phosphite was not mutagenic in Salmonella typhimurium strains TA98, TA100, TA1535, or TA1537 in the presence or absence of Aroclor 1254-induced male Sprague-Dawley rat or Syrian hamster liver S9. This chemical did not induce sex-linked recessive lethal mutations in Drosophila melanogaster. An audit of the experimental data was conducted for these carcinogenic studies on dimethyl hydrogen phosphite. No data discrepancies were found that influenced the final interpretations. Under the conditions of these gavage studies, there was clear evidence of carcinogenicity in male rats receiving dimethyl hydrogen phosphite, as shown by increased incidences of alveolar/bronchiolar adenomas, alveolar/bronchiolar carcinomas, and squamous cell carcinomas of the lung and of neoplasms of the forestomach. There was equivocal evidence of carcinogenicity in female F344/N rats receiving dimethyl hydrogen phosphite, as shown by marginally increased incidences of alveolar/bronchiolar carcinomas of the lung and of neoplasms of the stomach. There was no evidence of carcinogenicity in male or female B6C3F1 mice receiving dimethyl hydrogen phosphite at doses of 100 ogen phosphite at doses of 100 or 200 mg/kg for 103 weeks. Synonyms: phosphonic acid, dimethyl ester (9CI); dimethyl phosphite; dimethyl phosphorus acid; methyl phosphonate; dimethyl phosphonate; dimethoxyphosphine oxide; TL 585; DMHP; phosphorous acid, dimethyl ester; dimethylphosphite; dimethyl phosphonate; dimethylphosphorous acid; bis(hydroxymethyl) phosphine oxide


Transcription and enhancer profiling in human monocyte subsets.
Human blood monocytes comprise at least 3 subpopulations that differ in phenotype and function. Here, we present the first in-depth regulome analysis of human classical (CD14(++)CD16(-)), intermediate (CD14(+)CD16(+)), and nonclassical (CD14(dim)CD16(+)) monocytes. Cap analysis of gene expression adapted to Helicos single-molecule sequencing was used to map transcription start sites throughout the genome in all 3 subsets. In addition, global maps of H3K4me1 and H3K27ac deposition were generated for classical and nonclassical monocytes defining enhanceosomes of the 2 major subsets. We identified differential regulatory elements (including promoters and putative enhancers) that were associated with subset-specific motif signatures corresponding to different transcription factor activities and exemplarily validated novel downstream enhancer elements at the CD14 locus. In addition to known subset-specific features, pathway analysis revealed marked differences in metabolic gene signatures. Whereas classical monocytes expressed higher levels of genes involved in carbohydrate metabolism, priming them for anaerobic energy production, nonclassical monocytes expressed higher levels of oxidative pathway components and showed a higher mitochondrial routine activity. Our findings describe promoter/enhancer landscapes and provide novel insights into the specific biology of human monocyte subsets.


A new strategy for the treatment of sorafenib-refractory metastatic renal cell carcinoma in China: combination with intermittent chemotherapy.
This study assesses the clinical safety and efficacy of Gemcitabine and S-1 combination chemotherapy in sorafenib-refractory metastatic renal cell carcinoma (RCC) patients. The baseline characteristics and survival outcomes of 19 patients suffering from metastatic and progressive sorafenib-refractory RCC were retrospectively collected and analyzed from January 2010 to April 2014. Patients were treated by combining Gemcitabine (1,000 mg/m2, day 1 and day 8 of every cycle of 21 days) and S-1 (40 mg/m2, twice a day for 14 days, followed by the rest period of 7 days), with a continual treatment of sorafenib 400 mg twice a day in a cycle of 28 days. After combination chemotherapy, the disease control rate was 68.4%. Among them, 6 patients (31.6%) had progressive disease (PD), 5 patients (26.3%) had stable disease (SD) and 8 patients (42.1%) had partial response (PR). The median time to progression (TTP) was 6.3 months (range, 2.0-32.7 months), and the median overall survival (OS) was 19.7 months (range, 5.7-45.0 months). In the survival analysis, comparing PD group, disease control (PR + SD) group showed an obviously longer TTP (median TTP: 9.5 vs. 2.0 months, 95% CI, 7.7-11.3 months, P<0.001) and OS (median OS: 21.0 vs. 8.3 months, 95% CI, 14.5-24.9 months, P<0.001). In univariate and multivariate analysis, TTP and OS were significantly associated with disease control condition. Side-effects were found in all patients at different degree, but only 3 patients suffered grade 3/4 toxicities (15.8%). No death related to treatment was observed. The combination chemotherapy could be a promising treatment option for advanced metastatic RCC (mRCC) patients after sorafenib refractory.


Meiotic maturation induces animal-vegetal asymmetric distribution of aPKC and ASIP/PAR-3 in Xenopus oocytes.
The asymmetric distribution of cellular components is an important clue for understanding cell fate decision during embryonic patterning and cell functioning after differentiation. In C. elegans embryos, PAR-3 and aPKC form a complex that colocalizes to the anterior periphery of the one-cell embryo, and are indispensable for anterior-posterior polarity that is formed prior to asymmetric cell division. In mammals, ASIP (PAR-3 homologue) and aPKCgamma form a complex and colocalize to the epithelial tight junctions, which play critical roles in epithelial cell polarity. Although the mechanism by which PAR-3/ASIP and aPKC regulate cell polarization remains to be clarified, evolutionary conservation of the PAR-3/ASIP-aPKC complex suggests their general role in cell polarity organization. Here, we show the presence of the protein complex in Xenopus laevis. In epithelial cells, XASIP and XaPKC colocalize to the cell-cell contact region. To our surprise, they also colocalize to the animal hemisphere of mature oocytes, whereas they localize uniformly in immature oocytes. Moreover, hormonal stimulation of immature oocytes results in a change in the distribution of XaPKC 2-3 hours after the completion of germinal vesicle breakdown, which requires the kinase activity of aPKC. These results suggest that meiotic maturation induces the animal-vegetal asymmetry of aPKC.


Nut consumption and risk of coronary heart disease: a review of epidemiologic evidence.
Traditionally nuts have been perceived as an unhealthy food because of their high fat content. However, recent accumulative evidence suggests that frequent consumption of nuts may be protective against coronary heart disease (CHD). So far, five large prospective cohort studies (the Adventist Health Study, the Iowa Women Health Study, the Nurses' Health Study, the Physicians' Health Study, and the CARE Study) have examined the relation between nut consumption and the risk of CHD and all have found an inverse association. In addition, several clinical studies have observed beneficial effects of diets high in nuts (including walnuts, peanuts, almonds, and other nuts) on blood lipids. The beneficial effects of nut consumption observed in clinical and epidemiologic studies underscore the importance of distinguishing different types of fat. Most fats in nuts are mono- and polyunsaturated fats that lower low-density lipoprotein cholesterol level. Based on the data from the Nurses' Health Study, we estimated that substitution of the fat from 1 ounce of nuts for equivalent energy from carbohydrate in an average diet was associated with a 30% reduction in CHD risk and the substitution of nut fat for saturated fat was associated with 45% reduction in risk. Given the strong scientific evidence for the beneficial effects of nuts, it seems justifiable to move nuts to a more prominent place in the United States Department of Agriculture Food Guide Pyramid. Regular nut consumption can be recommended in the context of a healthy and balanced diet.


Incidence of self-reported brain injury and the relationship with substance abuse: findings from a longitudinal community survey.
Traumatic or serious brain injury (BI) has persistent and well documented adverse outcomes, yet 'mild' or 'moderate' BI, which often does not result in hospital treatment, accounts for half the total days of disability attributed to BI. There are currently few data available from community samples on the incidence and correlates of these injuries. Therefore, the study aimed to assess the 1) incidence of self-reported mild (not requiring hospital admission) and moderate (admitted to hospital)) brain injury (BI), 2) causes of injury 3) physical health scores and 4) relationship between BI and problematic alcohol or marijuana use. An Australian community sequential-cohort study (cohorts aged 20-24, 40-44 and 60-64 years at wave one) used a survey methodology to assess BI and substance use at baseline and four years later. Of the 7485 wave one participants, 89.7% were re-interviewed at wave two. There were 56 mild (230.8/100000 person-years) and 44 moderate BI (180.5/100000 person-years) reported between waves one and two. Males and those in the 20-24 year cohort had increased risk of BI. Sports injury was the most frequent cause of BI (40/100) with traffic accidents being a greater proportion of moderate (27%) than mild (7%) BI. Neither alcohol nor marijuana problems at wave one were predictors of BI. BI was not a predictor of developing substance use problems by wave two. BI were prevalent in this community sample, though the incidence declined with age. Factors associated with BI in community samples differ from those reported in clinical samples (e.g. typically traumatic brain injury with traffic accidents the predominate cause). Further, detailed evaluation of the health consequences of these injuries is warranted.


Heavy metal contamination of soil, sediment and water due to galena mining in Ebonyi State Nigeria: Economic costs of pollution based on exposure health risks.
In this study, the effect of galena mining with respect to heavy metal pollution of groundwater, surface water, soil and sediments in Enyimagalagu and Mkpuma-Akpatakpa Communities in Ebonyi State, Nigeria, was investigated to estimate the health and economic burden. The heavy metals were measured using atomic absorption spectrometry (AAS). The water quality of the groundwater and surface water was determined using the water quality index (WQI). The potential health burden was estimated by determining carcinogenic and non-carcinogenic health risks via risk index (RI) and hazard index (HI), respectively. The potential economic burden was estimated using the value of statistical life (VSL) and cost of illness (COI). Obtained results revealed that the WQI of the groundwater and surface water ranged from 197 to 327 indicating very poor to unsuitable water for drinking. No non-carcinogenic risks were associated with exposure to the soil and sediment components of the environment. However, there were non-carcinogenic risks associated with the surface and groundwater, with the HIs ranging from 1.8 to 5.4. Based on the carcinogenic risk threshold of 10-6, there were carcinogenic risks across all the environmental media ranging from 8.4*10-5 - 2.1*10-3. The economic cost of heavy metal pollution ranged from 20.7 million USD (10.35 billion) to 543.3 million USD (271.6 billion) for the VSL, whereas it ranged from 0.141 million USD (70.8 million) to 3.72 million USD (1.86 billion) for the COI. These costs are quite huge and can be avoided via pollution abatement measures.


Kinetic analysis of tautomer forms of aromatic-urea compounds with acetate ions: solvent effect of excited state intermolecular proton transfer.
In this paper, we report the solvent effect of excited state intermolecular proton transfer (ESIPT) reactions of urea compounds in the presence of tetrabutylammonium acetate (TBAAc). We prepared anthracene-urea compounds (9An and 2An), a pyrene-urea compound (Py) and an anthracene-diurea compound (9,10An), which have alkylsulfonyl groups to improve their solubility in various organic solvents. We investigated the solvent effects of the ESIPT reaction using absorption, fluorescence, and 1H NMR spectroscopy along with fluorescence decay measurements in dimethyl sulfoxide (DMSO), acetonitrile (MeCN), tetrahydrofuran (THF) and toluene. The tautomer fluorescence of 9An showed remarkable solvent dependence on the spectral red-shift compared with 2An, Py and 9,10An. As a result of the detailed spectroscopic investigations with regard to the solvent including kinetic analysis of the ESIPT for 9AnAcO-, we revealed that the energy gap between the normal and tautomer forms in the excited state depended on the hydrogen bond acceptor basicity (β), which is one of the Kamlet-Taft solvent parameters. Finally, we discovered that the tautomer structures of aromatic-urea compounds were stabilized by hydrogen bond interactions.


Investigation of Clostridium botulinum group III's mobilome content.
Clostridium botulinum group III is mainly responsible for botulism in animals. It could lead to high animal mortality rates and, therefore, represents a major environmental and economic concern. Strains of this group harbor the botulinum toxin locus on an unstable bacteriophage. Since the release of the first complete C. botulinum group III genome sequence (strain BKT015925), strains have been found to contain others mobile elements encoding for toxin components. In this study, seven assays targeting toxin genes present on the genetic mobile elements of C. botulinum group III were developed with the objective to better characterize C. botulinum group III strains. The investigation of 110 C. botulinum group III strains and 519 naturally contaminated samples collected during botulism outbreaks in Europe showed alpha-toxin and C2-I/C2-II markers to be systematically associated with type C/D bont-positive samples, which may indicate an important role of these elements in the pathogenicity mechanisms. On the contrary, bont type D/C strains and the related positive samples appeared to contain almost none of the markers tested. Interestingly, 31 bont-negative samples collected on farms after a botulism outbreak revealed to be positive for some of the genetic mobile elements tested. This suggests loss of the bont phage, either in farm environment after the outbreak or during laboratory handling.


The six-minute walk test in chronic pediatric conditions: a systematic review of measurement properties.
The Six-Minute Walk Test (6MWT) is increasingly being used as a functional outcome measure for chronic pediatric conditions. Knowledge about its measurement properties is needed to determine whether it is an appropriate test to use. The purpose of this study was to systematically review all published clinimetric studies on the 6MWT in chronic pediatric conditions. The databases MEDLINE, EMBASE, CINAHL, PEDro, and SPORTDiscus were searched up to February 2012. Studies designed to evaluate measurement properties of the 6MWT in a chronic pediatric condition were included in the systematic review. The methodological quality of the included studies and the measurement properties of the 6MWT were examined. A best evidence synthesis was performed on 15 studies, including 9 different chronic pediatric conditions. Limited evidence to strong evidence was found for reliability in various chronic conditions. Strong evidence was found for positive criterion validity of the 6MWT with peak oxygen uptake in some populations, but negative criterion validity was found in other populations. Construct validity remained unclear in most patient groups because of methodological flaws. Little evidence was available for responsiveness and measurement error. Studies showed large variability in test procedures despite existing guidelines for the performance of the 6MWT. Unavailability of a specific checklist to evaluate the methodological quality of clinimetric studies on performance measures was a limitation of the study. Evidence for measurement properties of the 6MWT varies largely among chronic pediatric conditions. Further research is needed in all patient groups to explore the ability of the 6MWT to measure significant and clinically important changes. Until then, changes measured with the 6MWT should be interpreted with caution. Future studies or consensus regarding modified test procedures in the pediatric population is recommended.


Selective expression of α-synuclein-immunoreactivity in vesicular acetylcholine transporter-immunoreactive axons in the guinea pig rectum and human colon.
Parkinson's disease is a neurodegenerative disorder characterized by motor and nonmotor impairments, including constipation. The hallmark pathological features of Parkinson's disease are Lewy bodies and neurites, of which aggregated α-synuclein is a major constituent. Frequently, Lewy pathology is identified in the distal gut of constipated Parkinson's disease patients. The neurons that innervate the distal gut that express α-synuclein have not been identified. We used multiple-labeling immunohistochemistry and anterograde tracing to quantify which neurons projecting to the guinea pig rectum and human colon expressed α-synuclein in their axons. α-Synuclein-immunoreactivity was present in 24 ± 0.7% of somatostatin (SOM)-immunoreactive (IR) varicosities; 20 ± 4.3% of substance P (SP)-IR varicosities and 9 ± 1.3% vasoactive intestinal polypeptide (VIP)-IR varicosities in guinea pig rectal myenteric ganglia. However, α-synuclein-immunoreactivity was localized in significantly more vesicular acetylcholine transporter (VAChT)-IR varicosities (88 ± 3%, P < 0.001). Of SOM-IR, SP-IR, and VIP-IR varicosities that lacked VAChT-immunoreactivity, only 1 ± 0.3%, 0 ± 0.3%, and 0% contained α-synuclein-immunoreactivity, respectively. 71 ± 0.8% of VAChT-IR varicosities in myenteric ganglia of human colon were α-synuclein-IR. In guinea pig rectal myenteric ganglia, α-synuclein- and VAChT-immunoreactivity coexisted in 15 ± 1.4% of biotinamide-labeled extrinsic varicosities; only 1 ± 0.3% of biotinamide-labeled extrinsic varicosities contained α-synuclein-immunoreactivity without VAChT-immunoreactivity. α-Synuclein expression in axons to the distal gut correlates closely with expression of the cholinergic marker, VAChT. This is the first report of cell-selective α-synuclein expression in the nervous system. Our results suggest cholinergic neurons in the gut may be vulnerable in Parkinson's disease.


Dip1 inhibits growth and gene transcription in MCF-7 breast cancer cells.
In previous studies we identified a novel gene Dipl, also designated CCNDBP1, which encodes a 42kDa helix-loop-helix (HLH) nuclear protein. Although this protein was originally identified by its ability to bind to cyclin D1 its precise biochemical functions are not known. In the present study we carried out mechanistic studies on Dip1 focusing on the human breast cancer cell line MCF-7. We found that overexpression of Dip1 in MCF-7 cells inhibited colony formation and cell proliferation. Reporter assays in MCF-7 cells indicated that Dip1 strongly inhibited the transcriptional activities of the cyclin D1, c-fos, NF-kappaB, SRE and p21cP1 promoters. Furthermore studies with truncated and mutant forms of the cyclin D1 promoter suggest that Dip1 does not act on specific transcriptional elements. Assays with mutant and truncated forms of Dip1 indicated that both the LXXLL motif and the HLH domain play important, but not exclusive, roles in these inhibitory effects. Dip1 co-immunoprecipitated with the histone deacetylase (HDAC) proteins HDAC1 and HDAC3. Nevertheless Dip1 markedly inhibited the stimulation of cyclin D1 promoter activity obtained with trichostatin A [1], an inhibitor of HDAC. Taken together these findings suggest that Dip1 functions as a general repressor of transcription. Although the precise mechanism by which Dip1 inhibits gene transcription and the growth of MCF-7 cells remain to be determined, the present results suggest that Dip1 is a candidate tumor suppressor gene.


Pneumatic tourniquets in extremity surgery.
Pneumatic tourniquets maintain a relatively bloodless field during extremity surgery, minimize blood loss, aid identification of vital structures, and expedite the procedure. However, they may induce an ischemia-reperfusion injury with potentially harmful local and systemic consequences. Modern pneumatic tourniquets are designed with mechanisms to regulate and maintain pressure. Routine maintenance helps ensure that these systems are working properly. The complications of tourniquet use include postoperative swelling, delay of recovery of muscle power, compression neurapraxia, wound hematoma with the potential for infection, vascular injury, tissue necrosis, and compartment syndrome. Systemic complications can also occur. The incidence of complications can be minimized by use of wider tourniquets, careful preoperative patient evaluation, and adherence to accepted principles of tourniquet use.


3D integration of photonic crystal devices: vertical coupling with a silicon waveguide.
Two integrated devices based on the vertical coupling between a photonic crystal microcavity and a silicon (Si) ridge waveguide are presented in this paper. When the resonator is coupled to a single waveguide, light can be spectrally extracted from the waveguide to free space through the far field emission of the resonator. When the resonator is vertically coupled to two waveguides, a vertical add-drop filter can be realized. The dropping efficiency of these devices relies on a careful design of the resonator. In this paper, we use a Fabry-Perot (FP) microcavity composed of two photonic crystal (PhC) slab mirrors. Thanks to the unique dispersion properties of slow Bloch modes (SBM) at the flat extreme of the dispersion curve, it is possible to design a FP cavity exhibiting two quasi-degenerate modes. This specific configuration allows for a coupling efficiency that can theoretically achieve 100%. Using 3D FDTD calculations, we discuss the design of such devices and show that high dropping efficiency can be achieved between the Si waveguides and the PhC microcavity.


Producing routine malaria data: an exploration of the micro-practices and processes shaping routine malaria data quality in frontline health facilities in Kenya.
Routine health information systems can provide near real-time data for malaria programme management, monitoring and evaluation, and surveillance. There are widespread concerns about the quality of the malaria data generated through routine information systems in many low-income countries. However, there has been little careful examination of micro-level practices of data collection which are central to the production of routine malaria data. Drawing on fieldwork conducted in two malaria endemic sub-counties in Kenya, this study examined the processes and practices that shape routine malaria data generation at frontline health facilities. The study employed ethnographic methods-including observations, records review, and interviews-over 18-months in four frontline health facilities and two sub-county health records offices. Data were analysed using a thematic analysis approach. Malaria data generation was influenced by a range of factors including human resource shortages, tool design, and stock-out of data collection tools. Most of the challenges encountered by health workers in routine malaria data generation had their roots in wider system issues and at the national level where the framing of indicators and development of data collection tools takes place. In response to these challenges, health workers adopted various coping mechanisms such as informal task shifting and use of improvised tools. While these initiatives sustained the data collection process, they also had considerable implications for the data recorded and led to discrepancies in data that were recorded in primary registers. These discrepancies were concealed in aggregated monthly reports that were subsequently entered into the District Health Information Software 2. Challenges to routine malaria data generation at frontline health facilities are not malaria or health information systems specific; they reflect wider health system weaknesses. Any interventions seeking to improve routine malaria data generation must look beyond just malaria or health information system initiatives and include consideration of the broader contextual factors that shape malaria data generation.


Sodium-glucose transporter 2 is a diagnostic and therapeutic target for early-stage lung adenocarcinoma.
The diagnostic definition of indeterminate lung nodules as malignant or benign poses a major challenge for clinicians. We discovered a potential marker, the sodium-dependent glucose transporter 2 (SGLT2), whose activity identified metabolically active lung premalignancy and early-stage lung adenocarcinoma (LADC). We found that SGLT2 is expressed early in lung tumorigenesis and is found specifically in premalignant lesions and well-differentiated adenocarcinomas. SGLT2 activity could be detected in vivo by positron emission tomography (PET) with the tracer methyl 4-deoxy-4-[18F] fluoro-alpha-d-glucopyranoside (Me4FDG), which specifically detects SGLT activity. Using a combination of immunohistochemistry and Me4FDG PET, we identified high expression and functional activity of SGLT2 in lung premalignancy and early-stage/low-grade LADC. Furthermore, selective targeting of SGLT2 with FDA-approved small-molecule inhibitors, the gliflozins, greatly reduced tumor growth and prolonged survival in autochthonous mouse models and patient-derived xenografts of LADC. Targeting SGLT2 in lung tumors may intercept lung cancer progression at early stages of development by pairing Me4FDG PET imaging with therapy using SGLT2 inhibitors.


Comparison of bimodal and bilateral cochlear implant users on speech recognition with competing talker, music perception, affective prosody discrimination, and talker identification.
Despite excellent performance in speech recognition in quiet, most cochlear implant users have great difficulty with speech recognition in noise, music perception, identifying tone of voice, and discriminating different talkers. This may be partly due to the pitch coding in cochlear implant speech processing. Most current speech processing strategies use only the envelope information; the temporal fine structure is discarded. One way to improve electric pitch perception is to use residual acoustic hearing via a hearing aid on the nonimplanted ear (bimodal hearing). This study aimed to test the hypothesis that bimodal users would perform better than bilateral cochlear implant users on tasks requiring good pitch perception. Four pitch-related tasks were used. 1. Hearing in Noise Test (HINT) sentences spoken by a male talker with a competing female, male, or child talker. 2. Montreal Battery of Evaluation of Amusia. This is a music test with six subtests examining pitch, rhythm and timing perception, and musical memory. 3. Aprosodia Battery. This has five subtests evaluating aspects of affective prosody and recognition of sarcasm. 4. Talker identification using vowels spoken by 10 different talkers (three men, three women, two boys, and two girls). Bilateral cochlear implant users were chosen as the comparison group. Thirteen bimodal and 13 bilateral adult cochlear implant users were recruited; all had good speech perception in quiet. There were no significant differences between the mean scores of the bimodal and bilateral groups on any of the tests, although the bimodal group did perform better than the bilateral group on almost all tests. Performance on the different pitch-related tasks was not correlated, meaning that if a subject performed one task well they would not necessarily perform well on another. The correlation between the bimodal users' hearing threshold levels in the aided ear and their performance on these tasks was weak. Although the bimodal cochlear implant group performed better than the bilateral group on most parts of the four pitch-related tests, the differences were not statistically significant. The lack of correlation between test results shows that the tasks used are not simply providing a measure of pitch ability. Even if the bimodal users have better pitch perception, the real-world tasks used are reflecting more diverse skills than pitch. This research adds to the existing speech perception, language, and localization studies that show no significant difference between bimodal and bilateral cochlear implant users.


Defining potential roles of Pb(2+) in neurotoxicity from a calciomics approach.
Metal ions play crucial roles in numerous biological processes, facilitating biochemical reactions by binding to various proteins. An increasing body of evidence suggests that neurotoxicity associated with exposure to nonessential metals (e.g., Pb(2+)) involves disruption of synaptic activity, and these observed effects are associated with the ability of Pb(2+) to interfere with Zn(2+) and Ca(2+)-dependent functions. However, the molecular mechanism behind Pb(2+) toxicity remains a topic of debate. In this review, we first discuss potential neuronal Ca(2+) binding protein (CaBP) targets for Pb(2+) such as calmodulin (CaM), synaptotagmin, neuronal calcium sensor-1 (NCS-1), N-methyl-d-aspartate receptor (NMDAR) and family C of G-protein coupled receptors (cGPCRs), and their involvement in Ca(2+)-signalling pathways. We then compare metal binding properties between Ca(2+) and Pb(2+) to understand the structural implications of Pb(2+) binding to CaBPs. Statistical and biophysical studies (e.g., NMR and fluorescence spectroscopy) of Pb(2+) binding are discussed to investigate the molecular mechanism behind Pb(2+) toxicity. These studies identify an opportunistic, allosteric binding of Pb(2+) to CaM, which is distinct from ionic displacement. Together, these data suggest three potential modes of Pb(2+) activity related to molecular and/or neural toxicity: (i) Pb(2+) can occupy Ca(2+)-binding sites, inhibiting the activity of the protein by structural modulation, (ii) Pb(2+) can mimic Ca(2+) in the binding sites, falsely activating the protein and perturbing downstream activities, or (iii) Pb(2+) can bind outside of the Ca(2+)-binding sites, resulting in the allosteric modulation of the protein activity. Moreover, the data further suggest that even low concentrations of Pb(2+) can interfere at multiple points within the neuronal Ca(2+) signalling pathways to cause neurotoxicity.


Transmission resonances of electromagnetic wave through metallic gratings: phase and field characterizations.
We investigate experimentally and numerically the transmission resonances of electromagnetic wave through a metallic grating of periodic slits as well as an array of subwavelength holes. The far-field transmission (magnitude and phase) spectra and the detection of surface electric field are used to characterize two kinds of transmission resonances (Fabry-Perot-like and structural factor resonance) occurring to the slit grating. In addition, the comparison between the slit grating and the subwavelength hole array reveals the effect of the aperture property on the phase and field of resonantly transmitted electromagnetic wave.