Attitudes of medical students towards conflict of interest: a national survey in France.
Following recent health scandals in France, the French parliament adopted law n°2011-2012 to regulate ties between physicians and the pharmaceutical industry. The law also requires pharmaceutical companies to publicize financial and other benefits given to medical students. In this context, we administered a survey to medical students in France, in an effort to identify priorities for future education regarding conflicts of interest (COI). This web-based survey encompassed knowledge about, training on, personal exposure to, and opinions on COI among preclinical and clinical students as well as residents. Two thousand one hundred and one (2,101) students participated. Although most students (64.6%) believed that they are able to define what a COI is, they failed to correctly identify several situations as COI (receiving a gift, being offered a meal, being invited to a conference). Most students reported feeling inadequately educated about COI (85.2%). Compared to other class levels, residents were more exposed to pharmaceutical sales representatives. This exposure is highly associated to receipt of gifts (OR 14.51, 95% CI 11.67-18.05). Medical students were aware of potential bias induced by COI with respect to drug prescriptions and research, but felt personally immune towards COI. In our survey, personal research performed by students was more likely to be associated with perception of potential bias on prescription for self (but not for others) than attending a lecture on COI. Promulgating laws that regulate ties between physicians/students and the pharmaceutical industry is a mandatory first step. However, complementary strategies should be implemented within medical schools, in particular, specific training about COI in early medical education.


SNeP: a tool to estimate trends in recent effective population size trajectories using genome-wide SNP data.
Effective population size (Ne ) is a key population genetic parameter that describes the amount of genetic drift in a population. Estimating Ne has been subject to much research over the last 80 years. Methods to estimate Ne from linkage disequilibrium (LD) were developed ~40 years ago but depend on the availability of large amounts of genetic marker data that only the most recent advances in DNA technology have made available. Here we introduce SNeP, a multithreaded tool to perform the estimate of Ne using LD using the standard PLINK input file format (.ped and.map files) or by using LD values calculated using other software. Through SNeP the user can apply several corrections to take account of sample size, mutation, phasing, and recombination rate. Each variable involved in the computation such as the binning parameters or the chromosomes to include in the analysis can be modified. When applied to published datasets, SNeP produced results closely comparable with those obtained in the original studies. The use of SNeP to estimate Ne trends can improve understanding of population demography in the recent past, provided a sufficient number of SNPs and their physical position in the genome are available. Binaries for the most common operating systems are available at https://sourceforge.net/projects/snepnetrends/.


National estimates of the inpatient burden of pediatric bipolar disorder in the United States.
Pediatric bipolar disorder (BPD) is a debilitating recurrent chronic mental illness, characterized by cycling states of depression, mania, hypomania, and mixed episodes. Similarly to adults, children and adolescents with BPD are typically treated with pharmacotherapy and adjunctive psychotherapy. Nevertheless, emergency-room visits and hospitalizations are common for those suffering from pediatric BPD. Previous studies have shown declining trends in mean inpatient costs and length of stay (LOS) in the hospital for children with BPD. The objectives of this study were to calculate national estimates of the annual burden of inpatient hospitalizations of children and adolescents with BPD in the United States; to describe and compare the mean burden across various patient characteristics, hospital characteristics, and key comorbidities associated with BPD; and to determine the independent effects of these factors on hospitalization costs. Hospitalizations for children and adolescents whose primary diagnosis was BPD were selected from the Kids' Inpatient Database (KID) in 2003 and 2006. The burden for each year was estimated as total number of days in the hospital and total costs. Mean costs were calculated overall and for subpopulations identified by patient and hospital characteristics and by the top six comorbidities found for BPD. Ordinary-least-squares regression models explaining cost were estimated for both 2003 and 2006, and the models were compared by way of a Chow statistical test. There were 39,136 (40,679) BPD in hospitalizations in 2003 (2006), with total associated costs of USD 176 (USD 233) million in 2003 (2006). The mean cost was USD 4,490 (USD 5,725), while the mean LOS was 8.12 (8.99) days in 2003 (2006). Factors associated with higher cost included youth (younger than 13), being black, being from a high-income family, having many diagnoses, being insured by Medicaid, living in the North East or West regions of the country, and having a long hospital stay. Post-traumatic stress disorder and oppositional defiant disorder were associated with higher costs in 2006. Declining trends in mean cost and LOS, documented in previous studies for children with BPD, persisted into 2003 but showed a slight reversal by 2006. Over the three years, mean LOS rose by a little less than one day, while mean cost (not adjusted for inflation) rose by USD 1,235. Children and adolescents insured through Medicaid tended to stay in the hospital longer and have higher costs than those children who were privately insured. Due to relatively few expensive inpatient procedures for BPD patients, pediatric BPD hospitalizations, relative to hospitalizations overall, were significantly more burdensome on average in terms of days spent in the hospital than in terms of cost. To the extent that early detection of the disease along with appropriate outpatient treatment can be achieved, there could be significant reductions in the risk of hospitalizations for children with BPD. Further studies should be conducted to determine if average LOS and mean hospitalization cost remain consistent with declining trends or whether the increase between 2003 and 2006 represents a trend reversal.


Psychosocial working conditions and the utilization of health care services.
While there is considerable theoretical and empirical evidence on how job stress affects physical and mental health, few studies have examined the association between job related stress and health care utilization. Using data from the Canadian National Population Health Survey from 2000 to 2008, this paper examines the association between stressful working conditions, as measured by the job strain model, and the utilization of health care services. A zero inflated negative binomial regression is used to examine the excess health care utilization due to job strain. Separate regressions are estimated for both males and females since studies have shown gender differences in health care utilization. Estimates for the whole population show that high or medium job strain has a positive and statistically significant association with the number of visits to both a general practitioner (GP) and a specialist (SP). On average, the number of GP visits is up to 26% more (IRR = 1.26, 95% CI = 1.19-1.31) for individuals with high strain jobs compared to those in the low job strain category. Similarly, SP visits are up to 27% more (IRR = 1.27, 95% CI = 1.14-142) for the high strain category. Results are quantitatively similar for males and females, save for medium strain. In general, findings are robust to the inclusion of workplace social support, health status, provincial and occupational-fixed effects. Job strain may be positively associated with the utilization of health care services. This suggests that improving psychosocial working conditions and educating workers on stress-coping mechanisms could be beneficial for the physical and mental health of workers.


Female-Specific Association Between Variants on Chromosome 9 and Self-Reported Diagnosis of Irritable Bowel Syndrome.
Genetic factors are believed to affect risk for irritable bowel syndrome (IBS), but there have been no sufficiently powered and adequately sized studies. To identify DNA variants associated with IBS risk, we performed a genome-wide association study (GWAS) of the large UK Biobank population-based cohort, which includes genotype and health data from 500,000 participants. We studied 7,287,191 high-quality single nucleotide polymorphisms in individuals who self-reported a doctor's diagnosis of IBS (cases; n = 9576) compared to the remainder of the cohort (controls; n = 336,499) (mean age of study subjects, 40-69 years). Genome-wide significant findings were further investigated in 2045 patients with IBS from tertiary centers and 7955 population controls from Europe and the United States, and a small general population sample from Sweden (n = 249). Functional annotation of GWAS results was carried out by integrating data from multiple biorepositories to obtain biological insights from the observed associations. We identified a genome-wide significant association on chromosome 9q31.2 (single nucleotide polymorphism rs10512344; P = 3.57 × 10-8) in a region previously linked to age at menarche, and 13 additional loci of suggestive significance (P < 5.0×10-6). Sex-stratified analyses revealed that the variants at 9q31.2 affect risk of IBS in women only (P = 4.29 × 10-10 in UK Biobank) and also associate with constipation-predominant IBS in women (P = .015 in the tertiary cohort) and harder stools in women (P = .0012 in the population-based sample). Functional annotation of the 9q31.2 locus identified 8 candidate genes, including the elongator complex protein 1 gene (ELP1 or IKBKAP), which is mutated in patients with familial dysautonomia. In a sufficiently powered GWAS of IBS, we associated variants at the locus 9q31.2 with risk of IBS in women. This observation may provide additional rationale for investigating the role of sex hormones and autonomic dysfunction in IBS.


Myths and Facts about Vitiligo: An Epidemiological Study.
Vitiligo is a pigmentary disorder associated with many disease conditions that necessitates multiple drug regimens, which make the treatment complicated. This stigmatic disease forces the patient to approach all system of medicines as well as alternative medicines of non proven value, which further worsens the situation. At the same time the nonadherence to the treatment reflects poor prognosis, which is misunderstood for lack of response resulting in poor faith to the medications. The aim of this work was to assess the patient compliance and the factors affecting, and to monitor the adverse effects as well as drug interactions. The study was carried out in the Institute of Applied Dermatology for a period of one year. Patient compliance was assessed using Morisky Medication Adherence Scale and found that 71% of the patients were low adherent to medications. Family support, faith in doctor, higher educational status and effectiveness of the treatment were some of the reasons for medication adherence whereas forgetfulness, feasibility, occupational problem, polypharmacy, longer duration of treatment and the feeling that the disease under is control were some of the reasons listed for nonadherence. Three adverse reactions were reported with narrow band ultraviolet B and topical tacrolimus therapy and they were categorized into possible and probable according to causality assessment by Naranjo scale. Five drug interactions were reported and the causality assessment was done using drug interaction probability scale. None of the reactions were serious or life threatening. The present study revealed the hurdles in providing safe and effective treatment to the patients and also it suggest the need of doing more research on this disease since there is a general belief that vitiligo is an incurable disease.


Cooperativity of the assembly process in a low concentration chromonic liquid crystal.
IR-806 is a near-infrared cyanine dye that undergoes a two-step assembly process in aqueous solutions. The final assemblies orientationally order into a liquid crystal at a very low concentration (∼0.6 wt % at room temperature). While the first step of the assembly process is continuous as the dye concentration or temperature is varied (isodesmic), the second step is more abrupt (cooperative). Because the absorption spectrum of IR-806 changes dramatically during the assembly process, careful equilibrium and kinetic absorption experiments are utilized to examine the details of the cooperative second step. These experiments involve changes in both concentration and temperature, allowing a close thermodynamic analysis of the assembly process. Both equilibrium and kinetic investigations reveal that the assembly process is highly cooperative and can be described by multiple models (for example, nucleation and growth) in the highly cooperative limit. The enthalpy associated with the growth process and the activation energy of the rate-limiting step during disassembly are determined. These findings have significant implications for the structure of the assemblies that form the liquid crystal phase in IR-806.


Mixed neuronal-glial tumor in the temporal lobe of an infant: a case report.
Tumors that arise in the temporal lobes of infants and spread to the neural system are limited to several diagnoses. Herein, we present an infantile case of a temporal tumor showing neuronal and glial differentiation. The patient was a 9-month-old boy with low body weight due to intrauterine growth retardation. At 9 months after birth, he presented partial seizures. Computed tomography scanning revealed a mass (35 * 40 mm) in the left temporal lobe. Isointensity was noted on magnetic resonance T1-weighted images and fluid attenuation inversion recovery images. The tumor was heterogeneously enhanced with gadolinium. Positron emission tomography showed high methionine uptake in the tumor. During surgery, the tumor, which was elastic and soft and bled easily, was gross totally resected. A moderately clear boundary was noted between the tumor and normal brain parenchyma. Histologically, the tumor mainly comprised a ganglioglioma-like portion and short spindle cells at different densities. The former was immunohistochemically positive for some kinds of neuronal markers including synaptophysin. The spindle cells were positive for glial fibrillary acidic protein, but desmoplasia was not observed. The tumor contained both neuronal and glial elements; the former were the main constituents of the tumor and included several ganglion-like cells. Because neuronal elements gradually transited to glial cells, a mixed neuronal-glial tumor was diagnosed. The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/2045126100982604.


Purified plant cell walls with adsorbed polyphenols alter porcine faecal bacterial communities during in vitro fermentation.
A substantial fraction of ingested polyphenols accumulate in the large intestine (LI), attached to undigested plant cell walls (PCW) (dietary fibre). Yet, whether these PCW-bound polyphenols alter the structure and function of the resident microbiota remains unclear. This study characterised bacterial populations during the in vitro fermentation of three standard polyphenols: ferulic acid (FER), (±)-catechin (CAT), and cyanidin-3-glucoside (CYAN), adsorbed individually or in combination to apple cell walls (ACW). During fermentation with porcine faeces, samples were collected at regular time-points (up to 72 hours) for bacterial 16S rRNA gene amplicon sequencing and fermentation end-product analyses (short-chain fatty acids and ammonium). The metabolic end-products differed to only a small extent between substrates, though significantly for propionate (P < 0.0001). Significant differences in microbial populations were noted between substrates tested (P < 0.0001). The presence of cyanidin-3-glucoside resulted in the most significant differences between bacterial communities during fermentation of the ACW substrate. Key microbes identified to be associated with the ACW with adsorbed polyphenols as well as individual polyphenols were: Phascolarctobacterium with ACW + FER and FER, the Lachnospiraceae family with ACW + CYAN, Parabacteroides with ACW + CYAN and CYAN, Collinsella and Coprococcus with ACW + CAT, and the Clostridiales order with ACW + CAT and CAT. This study has demonstrated the use of a simplified model to indicate any microbial effects of polyphenols associated with dietary fibre in whole fruits. This work has shown that individual polyphenols, or those adsorbed to PCW, have potentially very different effects on the gut bacteria. Future work could examine further polyphenols associated with a range of fresh fruits.


Overlapping promoters modulate Fnr- and ArcA-dependent anaerobic transcriptional activation of the focApfl operon in Escherichia coli.
The recently identified P6A promoter of the anaerobically inducible focApfl operon of Escherichia coll overlaps the Fnr (fumarate-nitrate reduction regulator)-dependent P6 promoter. The Fnr-binding site of P6 and the -35 hexamer sequence of P6A are shared between the promoters. Inactivation of P6A, through introduction of a -10 hexamer mutation, resulted in enhanced anaerobic induction of operon expression. The dependence on the ArcA (aerobic respiration control regulator) and Fnr transcription factors for anaerobic induction was tested for several focA-lacZ and pfl-lacZ gene fusions. Anaerobic induction became more dependent on Fnr in derivatives lacking a functional P6A promoter compared with wild-type constructs. Moreover, aerobic expression of the focA gene was reduced by the p6A mutation, as was the dependence on ArcA for anaerobic induction. Inactivation of P6 severely reduced Fnr-dependent anaerobic induction, in accord with previous findings. Transcription analyses demonstrated that a mutation in the -10 hexamer sequence of either P6A or P6 did not adversely affect transcription from the remaining promoter. Taken together, these results indicate that the P6A promoter moderates the Fnr-dependent activation of P6 through competition for RNA polymerase binding.


Macroscopic Quantities of Collective Brain Activity during Wakefulness and Anesthesia.
The study of states of arousal is key to understand the principles of consciousness. Yet, how different brain states emerge from the collective activity of brain regions remains unknown. Here, we studied the fMRI brain activity of monkeys during wakefulness and anesthesia-induced loss of consciousness. We showed that the coupling between each brain region and the rest of the cortex provides an efficient statistic to classify the two brain states. Based on this and other statistics, we estimated maximum entropy models to derive collective, macroscopic properties that quantify the system's capabilities to produce work, to contain information, and to transmit it, which were all maximized in the awake state. The differences in these properties were consistent with a phase transition from critical dynamics in the awake state to supercritical dynamics in the anesthetized state. Moreover, information-theoretic measures identified those parameters that impacted the most the network dynamics. We found that changes in the state of consciousness primarily depended on changes in network couplings of insular, cingulate, and parietal cortices. Our findings suggest that the brain state transition underlying the loss of consciousness is predominantly driven by the uncoupling of specific brain regions from the rest of the network.


Nucleosomal peptide epitopes for nephritis-inducing T helper cells of murine lupus.
Nucleosome-specific T helper (Th) cells provide major histocompatibility complex class II-restricted, cognate help to nephritogenic antinuclear autoantibody-producing B cells in lupus. However, the lupus Th cells do not respond when components of the nucleosome, such as free DNA or histones, are individually presented by antigen-presenting cells. Thus critical peptide epitopes for the pathogenic Th cells are probably protected during uptake and processing of the native nucleosome particle as a whole. Therefore, herein we tested 145 overlapping peptides spanning all four core histones in the nucleosome. We localized three regions in core histones, one in H2B at amino acid position 10-33 (H2B(10-33)), and two in H4, at position 16-39 (H4(16-39)) and position 71-94 (H4(71-94)), that contained the peptide epitopes recognized by the pathogenic autoantibody-inducing Th cells of lupus. The peptide autoepitopes also triggered the pathogenic Th cells of (SWR x NZB)F1 lupus mice in vivo to induce the development of severe lupus nephritis. The nucleosomal autoepitopes stimulated the production of Th1-type cytokines, consistent with immunoglobulin IgG2a, IgG2b, and IgG3 being the isotypes of nephritogenic autoantibodies induced in the lupus mice. Interestingly, the Th cell epitopes overlapped with regions in histones that contain B cell epitopes targeted by autoantibodies, as well as the sites where histones contact with DNA in the nucleosome. Identification of the disease-relevant autoepitopes in nucleosomes will help in understanding how the pathogenic Th cells of spontaneous systemic lupus erythematosus emerge, and potentially lead to the development of peptide-based tolerogenic therapy for this major autoimmune disease.


Polarization and image rotation induced by a rotating dielectric rod: an optical angular momentum interpretation.
When light is transmitted along the axis of a rotating glass rod, the polarization of the light is rotated through a small angle [Proc. R. Soc. London, Ser. A349, 423 (1976)]. Under the same conditions, we predict a rotation of the transmitted image by exactly the same angle. The treatment of the two effects in terms of light's spin and orbital angular momentum suggests that they share a common origin.


Covariation of deep Southern Ocean oxygenation and atmospheric CO2 through the last ice age.
No single mechanism can account for the full amplitude of past atmospheric carbon dioxide (CO2) concentration variability over glacial-interglacial cycles. A build-up of carbon in the deep ocean has been shown to have occurred during the Last Glacial Maximum. However, the mechanisms responsible for the release of the deeply sequestered carbon to the atmosphere at deglaciation, and the relative importance of deep ocean sequestration in regulating millennial-timescale variations in atmospheric CO2 concentration before the Last Glacial Maximum, have remained unclear. Here we present sedimentary redox-sensitive trace-metal records from the Antarctic Zone of the Southern Ocean that provide a reconstruction of transient changes in deep ocean oxygenation and, by inference, respired carbon storage throughout the last glacial cycle. Our data suggest that respired carbon was removed from the abyssal Southern Ocean during the Northern Hemisphere cold phases of the deglaciation, when atmospheric CO2 concentration increased rapidly, reflecting--at least in part--a combination of dwindling iron fertilization by dust and enhanced deep ocean ventilation. Furthermore, our records show that the observed covariation between atmospheric CO2 concentration and abyssal Southern Ocean oxygenation was maintained throughout most of the past 80,000 years. This suggests that on millennial timescales deep ocean circulation and iron fertilization in the Southern Ocean played a consistent role in modifying atmospheric CO2 concentration.


Direct and pulsed current annealing of p-MOSFET based dosimeter: the "MOSkin".
Contemporary radiation therapy (RT) is complicated and requires sophisticated real-time quality assurance (QA). While 3D real-time dosimetry is most preferable in RT, it is currently not fully realised. A small, easy to use and inexpensive point dosimeter with real-time and in vivo capabilities is an option for routine QA. Such a dosimeter is essential for skin, in vivo or interface dosimetry in phantoms for treatment plan verification. The metal-oxide-semiconductor-field-effect-transistor (MOSFET) detector is one of the best choices for these purposes, however, the MOSFETs sensitivity and its signal stability degrade after essential irradiation which limits its lifespan. The accumulation of positive charge on the gate oxide and the creation of interface traps near the silicon-silicon dioxide layer is the primary physical phenomena responsible for this degradation. The aim of this study is to investigate MOSFET dosimeter recovery using two proposed annealing techniques: direct current (DC) and pulsed current (PC), both based on hot charged carrier injection into the gate oxide of the p-MOSFET dosimeter. The investigated MOSFETs were reused multiple times using an irradiation-annealing cycle. The effect of the current-annealing parameters was investigated for the dosimetric characteristics of the recovered MOSFET dosimeters such as linearity, sensitivity and initial threshold voltage. Both annealing techniques demonstrated excellent results in terms of maintaining a stable response, linearity and sensitivity of the MOSFET dosimeter. However, PC annealing is more preferable than DC annealing as it offers better dose response linearity of the reused MOSFET and has a very short annealing time.


Sampling duration and freezing temperature influence the analysed gastric inositol phosphate composition of pigs fed diets with different levels of phytase.
This experiment was conducted to determine the effects of time and freezing temperature during sampling on gastric phytate (myo-inositol [MYO] hexakisphosphate [InsP6]), lower inositol phosphates (InsP2-5) and MYO concentrations in pigs fed diets containing different levels of phytase. Forty pigs were fed 1 of 4 wheat-barley diets on an ad libitum basis for 28 d. The diets comprised a nutritionally adequate positive control (PC), a similar diet but with Ca and P reduced by 1.6 and 1.24 g/kg, respectively (NC), and the NC supplemented with 500 (NC + 500) or 2,000 (NC + 2000) FTU phytase/kg. At the end of the experiment, chyme were collected from the stomach, thoroughly mixed and 2 subsamples (30 mL) were frozen immediately: one snap-frozen at -79 °C and the other at -20 °C. The remaining chyme were left to sit at room temperature (20 °C) and further subsamples were collected and frozen as above at 5, 10 and 15 min from the point of mixing. There were linear reductions in gastric InsP6 concentration over time during sampling (P < 0.001), irrespective of diet or freezing temperature. Moreover, InsP6 concentration was influenced by a diet × freezing temperature interaction (P < 0.05), with less InsP6 measured in chyme frozen at -20 °C than at -79 °C; however, this difference was greater in the control diets than the phytase supplemented diets. Freezing chyme at -79 °C recovered more ∑InsP2-5 + MYO than freezing at -20 °C in pigs fed phytase supplemented diets; however, this difference was not apparent in the diets without phytase (diet × freezing temperature, P < 0.01). It can be concluded that significant phytate hydrolysis occurs in the gastric chyme of pigs during sampling and processing, irrespective of supplementary phytase activity. Therefore, to minimise post-slaughter phytate degradation and changes in the gastric inositol phosphate profile, chyme should be snap-frozen immediately after collection.


Accumulation of aberrant CpG hypermethylation by Helicobacter pylori infection promotes development and progression of gastric MALT lymphoma.
Aberrant DNA hypermethylation is an important mechanism for the inactivation of tumor-related genes in human tumors. Gastric mucosa-associated lymphoid tissue (MALT) lymphomas arise from Helicobacter pylori-associated chronic gastritis; most patients are H. pylori-positive and eradication therapy is highly effective. In the present study, we used methylation-specific PCR to analyze the DNA methylation status of 11 tumor-related genes (Kip2, p16, hMLH-1, p15, p73, MGMT, DAPK, MINT1, MINT2, MINT31 and HCAD) in 21 specimens of MALT lymphoma, 5 specimens of MALT lymphoma with large cell component (high-grade MALT lymphoma), 15 specimens of diffuse large B-cell lymphoma (DLBCL), 8 specimens of complete remission of MALT lymphoma after eradication therapy, 5 specimens with no evidence of malignancy and PBMCs from 10 healthy donors. The average number of methylated genes was significantly greater in gastric lymphomas as compared to normal controls (P<0.001). The CpG island methylator phenotype (CIMP) was observed in 93.3% (14/15) of DLBCLs, 100% (5/5) of high-grade MALT lymphomas and 61.9% (13/21) of MALT lymphomas; in contrast, CIMP was not found in the control group (0%). The average number of methylated genes and the CIMP incidence significantly increased with H. pylori infection. Furthermore, aberrant CpG methylation of specific genes, such as p16, MGMT and MINT31, was consistently associated with H. pylori infection. These findings strongly suggest that H. pylori infection causes the aberrant DNA hypermethylation of specific genes and induces CIMP, which is an important epigenetic mechanism for the development and progression of gastric MALT lymphoma; additionally, our findings provide new epigenetic markers.


The Effects of Local Police Surges on Crime and Arrests in New York City.
The New York Police Department (NYPD) under Operation Impact deployed extra police officers to high crime areas designated as impact zones. Officers were encouraged to conduct investigative stops in these areas. City officials credited the program as one of the leading causes of New York City's low crime rate. We tested the effects of Operation Impact on reported crimes and arrests from 2004 to 2012 using a difference-in-differences approach. We used Poisson regression models to compare differences in crime and arrest counts before and after census block groups were designated as impact zones compared to census block groups in the same NYPD precincts but outside impact zones. Impact zones were significantly associated with reductions in total reported crimes, assaults, burglaries, drug violations, misdemeanor crimes, felony property crimes, robberies, and felony violent crimes. Impact zones were significantly associated with increases in total reported arrests, arrests for burglary, arrests for weapons, arrests for misdemeanor crimes, and arrests for property felony crimes. Impact zones were also significantly associated with increases in investigative stops for suspected crimes, but only the increase in stops made based on probable cause indicators of criminal behaviors were associated with crime reductions. The largest increase in investigative stops in impact zones was based on indicators of suspicious behavior that had no measurable effect on crime. The findings suggest that saturating high crime blocks with police helped reduce crime in New York City, but that the bulk of the investigative stops did not play an important role in the crime reductions. The findings indicate that crime reduction can be achieved with more focused investigative stops.


Harnessing citizen science through mobile phone technology to screen for immunohistochemical biomarkers in bladder cancer.
Immunohistochemistry (IHC) is often used in personalisation of cancer treatments. Analysis of large data sets to uncover predictive biomarkers by specialists can be enormously time-consuming. Here we investigated crowdsourcing as a means of reliably analysing immunostained cancer samples to discover biomarkers predictive of cancer survival. We crowdsourced the analysis of bladder cancer TMA core samples through the smartphone app 'Reverse the Odds'. Scores from members of the public were pooled and compared to a gold standard set scored by appropriate specialists. We also used crowdsourced scores to assess associations with disease-specific survival. Data were collected over 721 days, with 4,744,339 classifications performed. The average time per classification was approximately 15 s, with approximately 20,000 h total non-gaming time contributed. The correlation between crowdsourced and expert H-scores (staining intensity × proportion) varied from 0.65 to 0.92 across the markers tested, with six of 10 correlation coefficients at least 0.80. At least two markers (MRE11 and CK20) were significantly associated with survival in patients with bladder cancer, and a further three markers showed results warranting expert follow-up. Crowdsourcing through a smartphone app has the potential to accurately screen IHC data and greatly increase the speed of biomarker discovery.


Tocotrienol-rich fraction, [6]-gingerol and epigallocatechin gallate inhibit proliferation and induce apoptosis of glioma cancer cells.
Plant bioactives [6]-gingerol (GING), epigallocatechin gallate (EGCG) and asiaticoside (AS) and vitamin E, such as tocotrienol-rich fraction (TRF), have been reported to possess anticancer activity. In this study, we investigated the apoptotic properties of these bioactive compounds alone or in combination on glioma cancer cells. TRF, GING, EGCG and AS were tested for cytotoxicity on glioma cell lines 1321N1 (Grade II), SW1783 (Grade III) and LN18 (Grade IV) in culture by the (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxy-phenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt) (MTS) assay. With the exception of AS, combinations of two compounds were tested, and the interactions of each combination were evaluated by the combination index (CI) using an isobologram. Different grades of glioma cancer cells showed different cytotoxic responses to the compounds, where in 1321N1 and LN18 cells, the combination of EGCG + GING exhibited a synergistic effect with CI = 0.77 and CI = 0.55, respectively. In contrast, all combinations tested (TRF + GING, TRF + EGCG and EGCG + GING) were found to be antagonistic on SW1783 with CI values of 1.29, 1.39 and 1.39, respectively. Combined EGCG + GING induced apoptosis in both 1321N1 and LN18 cells, as evidenced by Annexin-V FITC/PI staining and increased active caspase-3. Our current data suggests that the combination of EGCG + GING synergistically induced apoptosis and inhibits the proliferation 1321N1 and LN18 cells, but not SW1783 cells, which may be due to their different genetic profiles.


Acquisition of Cry1Ac protein by non-target arthropods in Bt soybean fields.
Soybean tissue and arthropods were collected in Bt soybean fields in China at different times during the growing season to investigate the exposure of arthropods to the plant-produced Cry1Ac toxin and the transmission of the toxin within the food web. Samples from 52 arthropod species/taxa belonging to 42 families in 10 orders were analysed for their Cry1Ac content using enzyme-linked immunosorbent assay (ELISA). Among the 22 species/taxa for which three samples were analysed, toxin concentration was highest in the grasshopper Atractomorpha sinensis and represented about 50% of the concentration in soybean leaves. Other species/taxa did not contain detectable toxin or contained a concentration that was between 1 and 10% of that detected in leaves. These Cry1Ac-positive arthropods included a number of mesophyll-feeding Hemiptera, a cicadellid, a curculionid beetle and, among the predators, a thomisid spider and an unidentified predatory bug belonging to the Anthocoridae. Within an arthropod species/taxon, the Cry1Ac content sometimes varied between life stages (nymphs/larvae vs. adults) and sampling dates (before, during, and after flowering). Our study is the first to provide information on Cry1Ac-expression levels in soybean plants and Cry1Ac concentrations in non-target arthropods in Chinese soybean fields. The data will be useful for assessing the risk of non-target arthropod exposure to Cry1Ac in soybean.


Physical characterization of synthetic phosphatidylinositol dimannosides and analogues in binary systems with phosphatidylcholine.
Native phosphatidylinositol mannosides (PIMs) from the cell wall of Mycobacterium bovis (M. bovis) and synthetic analogues have been identified to exert immunostimulatory activities. These activities have been investigated using particulate delivery systems containing native mannosylated lipids or total lipid extracts. Limited work has been carried out examining the incorporation of individual PIM lipids into suitable particulate formulations such as liposomes. The present study explored the possibility of constructing phosphatidylcholine (PC)-based liposomes containing synthetic PIM analogues. A series of six phosphatidylinositol dimannosides (PIM(2)s) and phosphatidylglycerol dimannosides (PGM(2)s) was characterized in this study. Binary Langmuir monolayers are a useful approach for establishing pharmaceutical properties, such as lipid-lipid interactions in mixed monolayers, to facilitate the design of liposome-based delivery systems. In mixed films the phosphoglycolipids were found to be miscible with PC based on evaluation of collapse pressures and deviations of experimental molecular areas from calculated ideal values. Concanavalin A (ConA) agglutination confirmed the presence of mannosylated lipids on the surface of the liposomes. Physicochemical properties of liposomes were affected by the presence of 2% (w/w) of phosphoglycolipids with liposome stability being increased by incorporation of long-chain PIM(2) and PGM2. Overall, while membrane stability of the liposomes was found to be dependent on incorporation of the phosphoglycolipids, all formulations retained proteins in amounts making them suitable for delivery.


Control of wave-front propagation with diffractive elements.
In principle, diffractive elements can be designed to control a propagating wave in three dimensions, but no general procedure has been proposed. We present an iterative method that is suitable for the design of such diffractive elements. The resulting complex amplitude distribution will approach any arbitrary requirement, as much as is permitted by basic physical principles. The problem of "nondiffracting-beam" propagation is analyzed as a special case, and intensity peaks are generated that propagate as much as 4 m with a bounded width. The generality of the method, as compared with other techniques, is beams.


Metabolic syndrome in newly diagnosed type 2 diabetes mellitus using NCEP-ATP III, the Nnewi experience.
Type 2 diabetes is becoming epidemic and several studies have shown that diabetes is associated with increased co-morbidities and impaired functional health in the general adult population. Type 2 diabetes is one of the co-morbidities associated with metabolic syndrome that carries with it increased risk of cardiovascular disease and death. The purpose of this study is therefore to determine the prevalence of metabolic syndrome in newly diagnosed type 2 diabetes mellitus subjects seen at Nnewi South East Nigeria. This is a cross-sectional study in newly diagnosed diabetics attending a private hospital-Hope Specialist Hospital, Nnewi. One hundred and eighteen (118) newly diagnosed diabetic patients were recruited into the study consisting of those who on routine screening were found to have elevated blood glucose or were symptomatic of the disease and presented for treatment. Statistical analysis was carried out using SPSS version 13. Student's t-test was used for continuous variables, and a χ2 test was used for categorical variables. In the analyses a P- value of <0.05 was considered statistically significant. Of the 118 subjects, 25 were removed from the study because their samples were lost as a result of prolonged power outage leaving 93 subjects consisting of 47 males and 46 females. The mean (SD) and the range of age was 55.27 (12.55) years, 24-84 years; SBP 153.52 (29.83) mmHg,100-230 mmHg; DBP 94.23 (15.42) mmHg, 60-140 mmHg; TC 5.17 (1.4) mmol/L, 2.0-11.12 mmol/L; LDL-C 2.06 (1.55) mmol/L, 0.1-9.4 mmol/L; HDL-C 1.28 (0.48) mmol/L, 0.15-2.8 mmol/L; TG 1.75 (0.85) mmol/L, 0.50-5.0 mmol/L; BMI 30.30 (6.23) kg/m 2 , 17.84-49.12 kg/m 2 ; and WC of the general population mean (SD) 96.86 (7.16) cm, range 84-112 cm; for men 101.40 (3.88) cm, range 85-108 cm and for women 92.22 (6.77) cm, 84-112 cm. Metabolic syndrome was found in 62 (66.7%) subjects of which 26 (41.9%) were males and 36 (58.1%) were females (P < 0.019). The prevalence of different components of metabolic syndrome was as follows: hypertension was found in 75 (80.6%): 37 males and 38 females (P = 0.635), dyslipidemia in 31 (60.8%): 19 males and 12 females (P = 0.572). Obesity was found in 23 (45.1%): 8 males and 15 females (P < 0.014). Of the study subjects 33 had hypertension prior to the diagnosis of diabetes mellitus (DM). Seventeen males had hypertriglyceridemia against 11 females (P = 0.357). Equal number of males and females (11 each) had low HDL--C (-C (P = 0.603). The study shows that metabolic syndrome is highly prevalent in newly diagnosed type 2 diabetes patients and the most common risk factor is hypertension.


Employing imaginative rationality: using metaphor when discussing death.
The prevalence of metaphors in medicine is widely acknowledged. In a qualitative study exploring expectations of longevity, we observed repeated recourse to the imaginative rationality provided by metaphors to express perspectives on longevity and death. Bafflement, acceptance, uncertainty and distress were conveyed through metaphors, providing valuable insight into the internal healthcare frameworks of participants. Skilful use of imaginative rationality in the healthcare setting may illuminate the elusive and often eschewed topic of death in a way that fosters clarity and new understandings, and pave the way towards a better life, and death for patients. By becoming aware of the nuances contained within patients'-as well as their own-metaphors, clinicians may enhance patients' overall healthcare experience and avert unintended miscommunication.


Mental health services use by melanoma patients receiving adjuvant interferon: association of pre-treatment mental health care with early discontinuation.
Although high-dose interferon (hd-ifn) is the sole approved adjuvant systemic treatment for melanoma in many jurisdictions, it is toxic. We sought to assess the population-level effects of hd-ifn toxicity, particularly neuropsychiatric toxicity, hypothesizing that such toxicity would have the greatest effect on mental health services use in advanced resected melanoma. This retrospective population-based registry study considered all melanoma patients receiving adjuvant hd-ifn in Ontario during 2008-2012. Toxicity was investigated through health services use compatible with hd-ifn toxicity (for example, mental health physician billings). Using stage data reported from cancer centres about a subset of patients (stages iib-iiic), a propensity-matched analysis compared such service use in patients who did and did not receive hd-ifn. Associations between early hd-ifn discontinuation and health services use were examined. Of 718 melanoma patients who received hd-ifn, 12% were 65 years of age and older, and 83% had few or no comorbidities. One third of the patients experienced 1 or more toxicity-associated health care utilization events within 1 year of starting hd-ifn. Of 420 utilization events, 364 (87%) were mental health-related, with 54% being family practitioner visits, and 39% being psychiatrist visits. In the propensity-matched analysis, patients receiving hd-ifn were more likely than untreated matched controls to use a mental health service (p = 0.01), with 42% of the control group and 51% of the hd-ifn group using a mental health service in the period spanning the 12 months before to the 24 months after diagnosis. In the multivariable analysis, early drug discontinuation was more likely in the presence of pre-existing mental health issues (odds ratio: 2.0; 95% confidence limits: 1.1, 3.4). Stage iib-iiic melanoma patients carry a substantial burden of mental health services use whether or not receiving hd-ifn, highlighting an important survivorship issue for these patients. High-dose interferon is associated with more use of mental health services, and pre-treatment use of mental health services is associated with treatment discontinuation. That association should be kept in mind when hd-ifn is being considered.


Identifying and seeing beyond multiple sequence alignment errors using intra-molecular protein covariation.
There is currently no way to verify the quality of a multiple sequence alignment that is independent of the assumptions used to build it. Sequence alignments are typically evaluated by a number of established criteria: sequence conservation, the number of aligned residues, the frequency of gaps, and the probable correct gap placement. Covariation analysis is used to find putatively important residue pairs in a sequence alignment. Different alignments of the same protein family give different results demonstrating that covariation depends on the quality of the sequence alignment. We thus hypothesized that current criteria are insufficient to build alignments for use with covariation analyses. We show that current criteria are insufficient to build alignments for use with covariation analyses as systematic sequence alignment errors are present even in hand-curated structure-based alignment datasets like those from the Conserved Domain Database. We show that current non-parametric covariation statistics are sensitive to sequence misalignments and that this sensitivity can be used to identify systematic alignment errors. We demonstrate that removing alignment errors due to 1) improper structure alignment, 2) the presence of paralogous sequences, and 3) partial or otherwise erroneous sequences, improves contact prediction by covariation analysis. Finally we describe two non-parametric covariation statistics that are less sensitive to sequence alignment errors than those described previously in the literature. Protein alignments with errors lead to false positive and false negative conclusions (incorrect assignment of covariation and conservation, respectively). Covariation analysis can provide a verification step, independent of traditional criteria, to identify systematic misalignments in protein alignments. Two non-parametric statistics are shown to be somewhat insensitive to misalignment errors, providing increased confidence in contact prediction when analyzing alignments with erroneous regions because of an emphasis on they emphasize pairwise covariation over group covariation.


Sleep-disordered breathing: clinical features, pathophysiology and diagnosis.
In recent decades, the association between sleep-disordered breathing (SDB) and cardio- and cerebrovascular diseases (including hypertension, coronary heart disease and stroke) has been the focus of interest of both clinicians and researchers. A growing concern is the increasing prevalence of SDB in the general population, which can be partly explained by the rise in obesity prevalence and population aging, as well as by the development of enhanced diagnostic tools and approaches. Because of evidence of adverse long-term effects of SDB on cardiovascular morbidity and overall mortality, systematic screening for SDB should be considered for populations at risk. The evidence of a long-term benefit of treatment for SDB, however, is still controversial and the best management approaches are still unclear. This article summarises available epidemiological data and focuses on the main pathophysiological mechanisms linking SDB to cardio- and cerebrovascular disorders. We will also give a critical overview of the current diagnostic procedures. The available treatment approaches and their prognostic effects on cardio- and cerebrovascular health will be discussed in a second paper.


Presence of tumour inhibits the normal post-operative response in arginine and NO production in non-cachectic mice.
We have described recently that cancer patients have low plasma arginine concentrations, even without weight loss being present, suggesting that decreased arginine availability may be a specific feature of the presence of tumour. As arginine is important in post-operative repair, we hypothesized that abnormalities in arginine metabolism in cancer lead to an aberrant post-operative response in arginine and NO metabolism. To investigate this, we studied post-operative alterations in arginine and NO production and the acute-phase response in MCA (methylcholanthrene) sarcoma-bearing mice. Controls, mice with small MCA tumours (<15% of carcass weight) and large MCA tumours (>15% of carcass weight) were studied, either with or without undergoing laparotomy. The stable isotopes L-[guanidino-(15)N(2)-(2)H(2)]arginine and L-[ureido-(15)N]citrulline were used to study whole-body arginine and NO production rates. SAP (serum amyloid P component) concentrations were measured to assess the acute-phase response. Significance was tested using Mann-Whitney U test. In healthy FVB mice, laparotomy significantly increased whole-body arginine production (from 42+/-3 to 54+/-3 nmol x 10 g(-1) of carcass weight x min(-1)), NO production (from 1.1+/-0.1 to 1.4+/-0.2 nmol x 10 g(-1) of carcass weight x min(-1)) and levels of SAP (from 4+/-1 to 115+/-23 ng/ml), whereas in all MCA tumour-bearing mice baseline values of arginine metabolism and SAP concentration were already elevated and the response to laparotomy was absent. In conclusion, MCA tumour-bearing mice had a disturbed post-operative metabolic response, as evidenced by attenuated post-operative arginine and NO production, concomitant with an attenuated acute-phase response. This indicates that altered arginine metabolism may be an important characteristic of the metabolic changes in cancer.


Bedtime routines for young children: a dose-dependent association with sleep outcomes.
Establishment of a consistent bedtime routine (the activities that occur right before lights out) is often recommended as part of healthy sleep habits. However, no studies have investigated the dose-dependent association of a bedtime routine with sleep outcomes, especially in young children for whom they are particularly recommended. Thus, the aim of this study was to examine the associations of a consistent bedtime routine with sleep outcomes in young children (ages 0 through 5 y) in a large global sample and assess whether there is a dose-dependent relationship between the frequency of a bedtime routine both concurrently and retrospectively with sleep outcomes. Mothers of 10,085 children (Australia-New Zealand, Canada, China, Hong Kong, India, Japan, Korea, Malaysia, Philippines, Singapore, Thailand, United Kingdom, United States) completed the Brief Infant/Child Sleep Questionnaire. A consistent bedtime routine was associated with better sleep outcomes, including earlier bedtimes, shorter sleep onset latency, reduced night wakings, and increased sleep duration. Decreased parent-perceived sleep problems and daytime behavior problems were also related to institution of a regular bedtime routine. Furthermore, there was a dose-dependent relationship, with better outcomes associated with increased "doses" of having a bedtime routine, both currently and retrospectively, and was found within both predominantly Asian and predominantly Caucasian cultural regions. These results indicate that having a regular nightly bedtime routine is associated with improved sleep in young children, and suggests that the more consistently a bedtime routine is instituted and the younger started the better.


Pilot-scale fluoride-containing wastewater treatment by the ballasted flocculation process.
A pilot-scale ballasted flocculation system was used to remove fluoride from one type of industrial wastewater. The system included the formation of calcium fluoride (CaF2) using calcium hydroxide followed by coagulation sedimentation. Calcium fluoride was recycled as nuclei for enhancing CaF2 precipitation and as a ballasting agent for improving fluoride removal and flocculation efficiency. Factors affecting fluoride and turbidity removal efficiencies, including pH in the CaF2-reacting tank and coagulation-mixing tank, sludge recycling ratio, and dosages of FeCl3 and polyacrylamide (PAM), were investigated in the pilot-scale system. The recycled CaF2 precipitates improved CaF2 formation kinetics, enhanced fluoride removal and flocculation performance. Under the optimized condition, the ballast flocculation process reduced fluoride concentration from 288.9 to 10.67 mg/L and the turbidity from 129.6 NTU to below 2.5 NTU.


A search for protein biomarkers links olfactory signal transduction to social immunity.
The Western honey bee (Apis mellifera L.) is a critical component of human agriculture through its pollination activities. For years, beekeepers have controlled deadly pathogens such as Paenibacillus larvae, Nosema spp. and Varroa destructor with antibiotics and pesticides but widespread chemical resistance is appearing and most beekeepers would prefer to eliminate or reduce the use of in-hive chemicals. While such treatments are likely to still be needed, an alternate management strategy is to identify and select bees with heritable traits that allow them to resist mites and diseases. Breeding such bees is difficult as the tests involved to identify disease-resistance are complicated, time-consuming, expensive and can misidentify desirable genotypes. Additionally, we do not yet fully understand the mechanisms behind social immunity. Here we have set out to discover the molecular mechanism behind hygienic behavior (HB), a trait known to confer disease resistance in bees. After confirming that HB could be selectively bred for, we correlated measurements of this behavior with protein expression over a period of three years, at two geographically distinct sites, using several hundred bee colonies. By correlating the expression patterns of individual proteins with HB scores, we identified seven putative biomarkers of HB that survived stringent control for multiple hypothesis testing. Intriguingly, these proteins were all involved in semiochemical sensing (odorant binding proteins), nerve signal transmission or signal decay, indicative of the series of events required to respond to an olfactory signal from dead or diseased larvae. We then used recombinant versions of two odorant-binding proteins to identify the classes of ligands that these proteins might be helping bees detect. Our data suggest that neurosensory detection of odors emitted by dead or diseased larvae is the likely mechanism behind a complex and important social immunity behavior that allows bees to co-exist with pathogens.


Diversion of prescribed opioids by people living with chronic pain: results from an Australian community sample.
There has been an increase in prescription of opioids for chronic non-cancer pain, and concern exists over possible diversion of prescription opioids to the illicit marketplace. Recent media coverage suggests that elderly patients sell their prescribed opioids for additional income. This study investigated the extent to which an Australian community sample of chronic pain patients prescribed opioids reported supplying their prescribed opioids to others. Participants living with chronic non-cancer pain and prescribed opioids for their pain (n=952) were recruited across Australia via advertisements at pharmacies. A telephone interview included questions about their pain condition and opioid medication. Participants had been living with pain for a mean of 14.2 years; most common conditions included chronic back/neck problems and arthritis/rheumatism. Around half (43%) were currently prescribed one opioid, and 55% had been prescribed 2-5 opioids; the most common was oxycodone. Forty-two participants (4%) reported ever supplying prescribed opioids to another person; one participant reported receiving payment. Participants who supplied opioids to others were younger (odds ratio 0.97, 95% confidence interval 0.95-0.99) and engaged in a greater number of aberrant behaviours relating to their opioid medication (odds ratio 1.77, 95% confidence interval 1.45-2.17), including tampering with doses, taking opioids by alternative routes, seeing doctors to obtain extra opioids and refilling prescriptions early. Few people with chronic non-cancer pain divert their opioids to others. Media reports of elderly patients selling their opioids to supplement their income may be reflective of exceptional cases. Future studies may investigate the extent to which other patient groups divert prescription opioids to the illicit marketplace.


Fate Distribution and Regulatory Role of Human Mesenchymal Stromal Cells in Engineered Hematopoietic Bone Organs.
The generation of humanized ectopic ossicles (hOss) in mice has been proposed as an advanced translational and fundamental model to study the human hematopoietic system. The approach relies on the presence of human bone marrow-derived mesenchymal stromal cells (hMSCs) supporting the engraftment of transplanted human hematopoietic stem and progenitor cells (HSPCs). However, the functional distribution of hMSCs within the humanized microenvironment remains to be investigated. Here, we combined genetic tools and quantitative confocal microscopy to engineer and subsequently analyze hMSCs' fate and distribution in hOss. Implanted hMSCs reconstituted a humanized environment including osteocytes, osteoblasts, adipocytes, and stromal cells associated with vessels. By imaging full hOss, we identified rare physical interactions between hMSCs and human CD45+/CD34+/CD90+ cells, supporting a functional contact-triggered regulatory role of hMSCs. Our study highlights the importance of compiling quantitative information from humanized organs, to decode the interactions between the hematopoietic and the stromal compartments.


Induced basal normoglycemia and altered platelet aggregation in non-insulin-dependent diabetes.
Non-insulin-dependent diabetic subjects had abnormally raised in vitro platelet aggregation rates to collagen or ristocetin when thought to be "well-controlled" on diet alone but shown to have raised basal plasma glucose levels. Basal normoglycemia, induced with either ultralente insulin or chlorpropamide, was associated with a significant reduction of the enhanced platelet aggregation rates to normal. Some sulfonylurea drugs have been reported to have specific anti-platelet aggregatory properties, but the degree of plasma glucose control is probably more relevant.


Meta-narrative analysis of sports injury reporting practices based on the Injury Definitions Concept Framework (IDCF): A review of consensus statements and epidemiological studies in athletics (track and field).
Consistency in routines for reporting injury has been a focus of development efforts in sports epidemiology for a long time. To gain an improved understanding of current reporting practices, we applied the Injury Definitions Concept Framework (IDCF) in a review of injury reporting in a subset of the field. Meta-narrative review. An analysis of injury definitions reported in consensus statements for different sports and studies of injury epidemiology in athletics (track and field) published in PubMed between 1980 and 2013 was performed. Separate narratives for each of the three reporting contexts in the IDCF were constructed from the data. Six consensus statements and 14 studies reporting on athletics injury epidemiology fulfilled the selection criteria. The narratives on sports performance, clinical examination, and athlete self-report contexts were evenly represented in the eligible studies. The sports performance and athlete self-report narratives covered both professional and community athletes as well as training and competition settings. In the clinical examination narrative, data collection by health service professionals was linked to studies of professional athletes at international championships. From an application of the IDCF in a review of injury reporting in sports epidemiology we observed a parallel usage of reporting contexts in this field of research. The co-existence of reporting methodologies does not necessarily reflect a problematic situation, but only provided that firm precautions are taken when comparing studies performed in the different contexts.


Binocular neurons in V1 of awake monkeys are selective for absolute, not relative, disparity.
Most neurophysiological accounts of disparity selectivity in neurons of the primary visual cortex (V1) imply that they are selective for absolute retinal disparities. By contrast, a number of psychophysical observations indicate that relative disparities play a more important role in depth perception. During recordings from disparity selective neurons in area V1 of awake behaving monkeys, we used a disparity feedback loop () to add controlled amounts of absolute disparity to a display containing both absolute and relative disparities. This manipulation changed the absolute disparity of all the visible features in the display but left unchanged the relative disparities signalled by these features. The addition of absolute disparities produced clear changes in the neural responses to unchanged external stimuli, which were well predicted by the measured change in absolute disparity: in 45/53 cases, the neuron maintained a consistent firing pattern with respect to absolute disparity so that the manipulation created no significant change in the absolute disparity preferred by the neuron. No neuron in V1 maintained a consistent relationship with relative disparity. We conclude that the relative disparity signals used in primate depth perception are constructed outside area V1.


Inverse correlation between tyrosine phosphorylation and collagenase production in chondrocytes.
Collagenase production by chondrocytes appears to play a major role in the development of osteoarthritis. Although the mechanisms regulating collagenase production by chondrocytes are not known, incubation of bovine chondrocytes in serum markedly decreases collagenase production. Since serum has been demonstrated to increase levels of phosphotyrosine (P-Tyr) in several cell types, we determined the effect of altering intracellular levels of P-Tyr on collagenase production. Both orthovanadate, a potent inhibitor of tyrosine phosphatases, and serum caused a marked increase in tyrosine phosphorylation. The increase in P-Tyr was associated with a decrease in the production of collagenase, suggesting that two processes may be linked. Orthovanadate caused an increase in P-Tyr in the absence of serum, suggesting that P-Tyr levels in resting chondrocytes are regulated through activity of both tyrosine kinases and phosphatases. Orthovanadate and serum induced a synergistic increase in P-Tyr levels, suggesting that serum functions through increasing kinase activity rather than decreasing phosphatase activity. In the absence of serum, concentrations of orthovanadate which maximally inhibited collagenase production primarily increased phosphorylation of a 36 kDa protein, suggesting that the phosphorylation of this protein may play a major role in regulating collagenase production. Orthovanadate had limited effects on chondrocyte proteoglycan synthesis, morphology or viability in the presence or absence of serum, suggesting that the decrease in collagenase production was not due to non-specific inhibition of protein synthesis or cellular toxicity. Inhibition of tyrosine phosphatases by orthovanadate or activation of tyrosine kinases by addition of serum correlated with the inhibition of collagenase production.


Absence of Borrelia burgdorferi in the myocardium of subjects with normal left ventricular systolic function: a study using PCR and electron microscopy.
Several studies have demonstrated the presence of the Borrelia burgdorferi (Bb) genome in the myocardium of patients with dilated cardiomyopathy (DCM). To further support a causal relationship between the presence of Bb in the heart muscle and the development of DCM, demonstration of the absence of Bb in the myocardium of subjects with normal left ventricular (LV) systolic function is needed. To determine the prevalence of Bb by polymerase chain reaction (PCR) and electron microscopy (EM) in individuals with normal LV systolic function and no history suggestive of myocarditis. We investigated 50 patients (67 ± 9 years, 15 women) with normal LV ejection fraction (EF) ≥ 50% undergoing cardiac surgery. During surgery, four samples from the right atrial appendage were obtained and subsequently examined by PCR and EM for the presence of Bb, and by immunohistochemistry to detect inflammatory cells. Serological testing of antibodies against Bb was also performed. Neither PCR nor EM detected Bb in any of the subjects. Immunohistological examination revealed myocardial inflammation in 2 individuals (4%). Serological analysis by enzyme-linked immunosorbent assay demonstrated IgM antibodies against Bb in 4% and IgG antibodies in 12% of the study cohort; Western blot revealed IgM as well as IgG positivity in 14% of patients. The absence of Bb in the myocardium of individuals who undergo cardiac surgery and have normal LV systolic function supports the idea of Bb pathogenicity in the development of DCM.


α Integrin cytoplasmic tails have tissue-specific roles during C. elegans development.
Integrin signaling impacts many developmental processes. The complexity of these signals increases when multiple, unique integrin heterodimers are expressed during a single developmental event. Since integrin heterodimers have different signaling capabilities, the signals originating at each integrin type must be separated in the cell. C. elegans have two integrin heterodimers, α INA-1/β PAT-3 and α PAT-2/β PAT-3, which are expressed individually or simultaneously, based on tissue type. We used chimeric α integrins to assess the role of α integrin cytoplasmic tails during development. Chimeric integrin ina-1 with the pat-2 cytoplasmic tail rescued lethality and maintained neuron fasciculation in an ina-1 mutant. Interestingly, the pat-2 tail was unable to completely restore distal tip cell migration and vulva morphogenesis. Chimeric integrin pat-2 with the ina-1 cytoplasmic tail had a limited ability to rescue a lethal mutation in pat-2, with survivors showing aberrant muscle organization, yet normal distal tip cell migration. In a wild type background, α integrin pat-2 with the ina-1 cytoplasmic tail had a dominant negative effect which induced muscle disorganization, cell migration defects and lethality. These results show the α integrin cytoplasmic tails impact unique cellular behaviors that vary by tissue type during development.


Correlation of humoral immune response with clinical presentation, pulmonary lesions and mortality patterns of goats experimentally infected with peste des petits ruminants virus.
The patterns of humoral immune response, measured by enzyme-linked immunosorbent assay and the development of clinical signs, pulmonary lesions and mortality patterns were studied in goats experimentally infected with peste des petits ruminants virus (PPRV) or Kata virus. It was possible to classify the animals into high and low responders according to the pattern of humoral immune response. The high responders had a prolonged, chronic infection characterized by a giant cell pneumonia which was sometimes complicated by bronchopneumonia. Such animals survived beyond 1 month. The low immune responders had a subacute or acute clinical presentation. In the former case, the animals developed an uncomplicated giant cell pneumonia and died within 1 month of infection. Those with the acute symptoms developed pulmonary congestion and oedema and succumbed to the infection in 1 week. The clinical and pathological response of goats to PPRV infection, and ultimately the outcome of the infection correlated well with the ability of the goats to mount specific antibodies to PPRV.


Regional myocardial infarction at operation. An automated system of identification.
The difference between normal and infarcted myocardium at operation cannot always be defected by inspection or palpation. Infarcted myocardium may be identified by a decrease in the amplitude of the ventricular bipolar electrogram. Although this method is reliable and reproducible, it requires a second observer's visual analysis and interpretation of the electrogram signal. This method is therefore subject to the vagaries of human observation, analysis, and accounts of rapidly changing data. We have designed and built an automated instrument to simplify the recognition of transmural infarction.


Spatial patterns and determinants of malaria infection during pregnancy in Zambia.
Malaria in pregnancy (MiP) is a major concern in Zambia. Here we aim to determine the burden and risk factors of MiP. Monthly reported district-level malaria cases among pregnant women (count data) from January 2009 to December 2014 were obtained from the Zambian District Health Information System. Negative binomial regression model was used to investigate the associations between vector control tools, coverage of health care facilities, transportation networks and population density. Data on MiP treatment were obtained from the 2012 Zambian Malaria Indicator Survey. Yearly clusters of MiP were investigated using spatial statistics in ArcGIS v 10.1. The results indicated that MiP decreased in Zambia between 2010 and 2013. MiP was observed throughout the year, but showed a strong seasonal pattern. Persistent hotspots of MiP were reported in the southeast and northeast regions of Zambia, with districts that had better access to rail road and presence of water bodies associated with decreased prevalence of MiP. Better indoor residual spraying and long-lasting insecticide-treated nets coverage was demonstrated to be protective against MiP. Mapping the distribution of MiP to track the future requirements for scaling up essential disease-prevention efforts in stable hotspots can help the Zambian National Malaria Control Center to further develop strategies to reduce malaria prevalence in this vulnerable sub-population.


Molecular evidence for early activity-dependent development of hamster motor neurons.
Monoclonal antibody Cat-301 recognizes a surface antigen on subsets of neurons in many areas of the mammalian CNS, including Y-cells in the cat dorsal lateral geniculate nucleus (LGN) and spinal motor neurons in several species. We have shown previously that the Cat-301 antigen is expressed relatively late in postnatal development, with a time course that matches that of late developmental features of both LGN and spinal cord neurons. The developmental time course of the expression of the Cat-301 antigen in the LGN correlates with the period during which visual deprivation can alter LGN Y-cells. Neonatal visual deprivation (by monocular lid suture or dark rearing) suppresses Cat-301 expression on Y-cells, while deprivation in adult animals has no effect on antigen expression. These results suggested that the onset of Cat-301 immunoreactivity provides a positive molecular marker for the end of a critical period in cat visual system development. To determine if Cat-301 might be a general marker for experience-dependent development in other areas of the CNS we have examined antigen expression on hamster spinal cord motor neurons. Here, we report that Cat-301 immunoreactivity develops on hamster motor neurons between postnatal days 7 and 14. Altering neuromuscular activity by sciatic nerve crush or thoracic hemicordotomy inhibits Cat-301 expression on motor neurons if performed before the onset of Cat-301 immunoreactivity. Other motor neuron antigens are unaffected by this procedure. In adult animals, nerve crush or cordotomy has no effect on Cat-301 immunoreactivity, demonstrating that Cat-301 expression is not simply dependent on ongoing neural activity. These observations suggest that motor neurons, like LGN neurons, require some pattern of neuronal activity during a critical period in development and, further, that the phenotypic changes in neurons consequent to early activity are reflected by the expression of specific molecules. The identification and characterization of such molecules may yield a description of the molecular mechanisms of experience-dependent development.


Right thoracic curvature in the normal spine.
Trunk asymmetry and vertebral rotation, at times observed in the normal spine, resemble the characteristics of adolescent idiopathic scoliosis (AIS). Right thoracic curvature has also been reported in the normal spine. If it is determined that the features of right thoracic side curvature in the normal spine are the same as those observed in AIS, these findings might provide a basis for elucidating the etiology of this condition. For this reason, we investigated right thoracic curvature in the normal spine. For normal spinal measurements, 1,200 patients who underwent a posteroanterior chest radiographs were evaluated. These consisted of 400 children (ages 4-9), 400 adolescents (ages 10-19) and 400 adults (ages 20-29), with each group comprised of both genders. The exclusion criteria were obvious chest and spinal diseases. As side curvature is minimal in normal spines and the range at which curvature is measured is difficult to ascertain, first the typical curvature range in scoliosis patients was determined and then the Cobb angle in normal spines was measured using the same range as the scoliosis curve, from T5 to T12. Right thoracic curvature was given a positive value. The curve pattern was organized in each collective three groups: neutral (from -1 degree to 1 degree), right (> +1 degree), and left (< -1 degree). In child group, Cobb angle in left was 120, in neutral was 125 and in right was 155. In adolescent group, Cobb angle in left was 70, in neutral was 114 and in right was 216. In adult group, Cobb angle in left was 46, in neutral was 102 and in right was 252. The curvature pattern shifts to the right side in the adolescent group (p < 0.01) and in adult group (p < 0.001) compared to the child group. There was no significant difference in curvature pattern between adolescent and adult group. Based on standing chest radiographic measurements, a right thoracic curvature was observed in normal spines after adolescence.


Cryptic Diversity in the Widespread Asian Ant Crematogaster rothneyi (Hymenoptera: Formicidae) Inferred from Morphological and Genetic Evidence.
The myrmicine species Crematogaster rothneyi is one of the most widely distributed ants in Asia, but it has rarely been collected in the field. Its distribution range covers South and Southeast Asia, extending approximately 5,000 km from India in the west to Sulawesi in the east. Despite this wide distribution range, C. rothneyi has been treated as a single taxonomic species, and no combined morphological or molecular analysis has been conducted to assess whether any intraspecific variation exists. The sequence divergences of C. rothneyi populations, mainly obtained from Southeast Asia, were investigated by analyzing 387 bp and 175 bp sequences of the 12S ribosomal RNA and cytochrome c oxidase subunit (COI) genes, respectively. Phylogenetic analysis indicated that the C. rothneyi populations were separated into three groups: group I from Thailand and Cambodia, group II from Bangladesh and Myanmar, and group III from Krakatau and Sulawesi. Groups II and III were recovered as a single clade, sister to group I. The interspecific divergences were 7.3% to 8.5% for 12S and 14.5% to 23.3% for COI between most C. rothneyi specimens and Cambodian specimens, while divergence for 12S was 3.5% between Thai and Cambodian specimens. The Thai specimens are not morphologically differentiated, and are considered conspecific to C. rothneyi. We describe the Cambodian series as a new species, Crematogaster yaharai sp. nov., based on unique antennal morphology and mesosomal sculpture patterns with molecular evidence. Crematogaster rothneyi civa Forel, 1902 is synonymized under C. rothneyi. Crematogaster rothneyi is widespread and has sister species, suggesting recent diversification within the Indochinese Peninsula.


Regulation of Dlx5 and Dlx6 gene expression by p63 is involved in EEC and SHFM congenital limb defects.
The congenital malformation Split Hand-Foot Malformation (SHFM, or ectrodactyly) is characterized by a medial cleft of hands and feet, and missing central fingers. Five genetically distinct forms are known in humans; the most common (type-I) is linked to deletions of DSS1 and the distalless-related homeogenes DLX5 and DLX6. As Dlx5;Dlx6 double-knockout mice show a SHFM-like phenotype, the human orthologs are believed to be the disease genes. SHFM-IV and Ectrodactyly-Ectodermal dysplasia-Cleft lip (EEC) are caused by mutations in p63, an ectoderm-specific p53-related transcription factor. The similarity in the limb phenotype of different forms of SHFM may underlie the existence of a regulatory cascade involving the disease genes. Here, we show that p63 and Dlx proteins colocalize in the nuclei of the apical ectodermal ridge (AER). In homozygous p63- (null) and p63EEC (R279H) mutant limbs, the AER fails to stratify and the expression of four Dlx genes is strongly reduced; interestingly, the p63+/EEC and p63+/- hindlimbs, which develop normally and have a normally stratified AER, show reduced Dlx gene expression. The p63+/EEC mutation combined with an incomplete loss of Dlx5 and Dlx6 alleles leads to severe limb phenotypes, which are not observed in mice with either mutation alone. In vitro, DeltaNp63alpha induces transcription from the Dlx5 and Dlx6 promoters, an activity abolished by EEC and SHFM-IV mutations, but not by Ankyloblepharon-Ectodermal defects-Cleft lip/palate (AEC) mutations. ChIP analysis shows that p63 is directly associated with the Dlx5 and Dlx6 promoters. Thus, our data strongly implicate p63 and the Dlx5-Dlx6 locus in a pathway relevant in the aetio-pathogenesis of SHFM.


The Polycomb-Group Repressor MEDEA Attenuates Pathogen Defense.
Plants recruit positive and negative regulators for fine tuning the balance between growth and development. Negative regulators of pathogen defense generally modulate defense hormone biosynthesis and signaling. Here, we report a mechanism for attenuation of the defense response in Arabidopsis (Arabidopsis thaliana), which is mediated by the polycomb-group repressor MEDEA (MEA). Our results showed that pathogen inoculation or exogenous application of salicylic acid, methyl jasmonate, or the bacterial 22-amino acid domain of flagellin peptide induces the expression of MEAMEA expression was higher when plants were inoculated with the avirulent strain of Pseudomonas syringae pv. tomato (Pst) carrying the AvrRpt2 effector (Pst-AvrRpt2) compared to the virulent Pst strain. MEA remains suppressed during the vegetative phase via DNA and histone (H3K27) methylation, and only the maternal copy is expressed in the female gametophyte and endosperm via histone and DNA demethylation. In contrast, Pst-AvrRpt2 induces high levels of MEA expression via hyper-accumulation of H3K4me3 at the MEA locus. MEA-overexpressing transgenic plants are susceptible to the fungal pathogen Botrytis cinerea and bacterial pathogens Pst and Pst-AvrRpt2, whereas mea mutant plants are more resistant to bacterial pathogens. AvrRpt2-mediated immunity requires the function of RESISTANCE TO P. SYRINGAE2 (RPS2) in Arabidopsis. Using transcriptional analysis and chromatin immunoprecipitation, we established that MEA directly targets RPS2 and suppresses its transcription. We screened an Arabidopsis cDNA library using MEA as the bait in a yeast two-hybrid assay and identified DROUGHT-INDUCED19, a transcription factor that interacts with MEA and recruits it at the RPS2 promoter. The results identified a previously unknown mechanism of defense response attenuation in plants.


Effect of crizotinib on overall survival in patients with advanced non-small-cell lung cancer harbouring ALK gene rearrangement: a retrospective analysis.
ALK gene rearrangement defines a new molecular subtype of non-small-cell lung cancer (NSCLC). In a recent phase 1 clinical trial, the ALK tyrosine-kinase inhibitor (TKI) crizotinib showed marked antitumour activity in patients with advanced, ALK-positive NSCLC. To assess whether crizotinib affects overall survival in these patients, we did a retrospective study comparing survival outcomes in crizotinib-treated patients in the trial and crizotinib-naive controls screened during the same time period. We examined overall survival in patients with advanced, ALK-positive NSCLC who enrolled in the phase 1 clinical trial of crizotinib, focusing on the cohort of 82 patients who had enrolled through Feb 10, 2010. For comparators, we identified 36 ALK-positive patients from trial sites who were not given crizotinib (ALK-positive controls), 67 patients without ALK rearrangement but positive for EGFR mutation, and 253 wild-type patients lacking either ALK rearrangement or EGFR mutation. To assess differences in overall survival, we assessed subsets of clinically comparable ALK-positive and ALK-negative patients. Among 82 ALK-positive patients who were given crizotinib, median overall survival from initiation of crizotinib has not been reached (95% CI 17 months to not reached); 1-year overall survival was 74% (95% CI 63-82), and 2-year overall survival was 54% (40-66). Overall survival did not differ based on age, sex, smoking history, or ethnic origin. Survival in 30 ALK-positive patients who were given crizotinib in the second-line or third-line setting was significantly longer than in 23 ALK-positive controls given any second-line therapy (median overall survival not reached [95% CI 14 months to not reached] vs 6 months [4-17], 1-year overall survival 70% [95% CI 50-83] vs 44% [23-64], and 2-year overall survival 55% [33-72] vs 12% [2-30]; hazard ratio 0·36, 95% CI 0·17-0·75; p=0·004). Survival in 56 crizotinib-treated, ALK-positive patients was similar to that in 63 ALK-negative, EGFR-positive patients given EGFR TKI therapy (median overall survival not reached [95% CI 17 months to not reached] vs 24 months [15-34], 1-year overall survival 71% [95% CI 58-81] vs 74% [61-83], and 2-year overall survival 57% [40-71] vs 52% [38-65]; p=0·786), whereas survival in 36 crizotinib-naive, ALK-positive controls was similar to that in 253 wild-type controls (median overall survival 20 months [95% CI 13-26] vs 15 months [13-17]; p=0·244). In patients with advanced, ALK-positive NSCLC, crizotinib therapy is associated with improved survival compared with that of crizotinib-naive controls. ALK rearrangement is not a favourable prognostic factor in advanced NSCLC. Pfizer Inc, V Foundation for Cancer Research.


Algivore or phototroph? Plakobranchus ocellatus (Gastropoda) continuously acquires kleptoplasts and nutrition from multiple algal species in nature.
The sea slug Plakobranchus ocellatus (Sacoglossa, Gastropoda) retains photosynthetically active chloroplasts from ingested algae (functional kleptoplasts) in the epithelial cells of its digestive gland for up to 10 months. While its feeding behavior has not been observed in natural habitats, two hypotheses have been proposed: 1) adult P. ocellatus uses kleptoplasts to obtain photosynthates and nutritionally behaves as a photoautotroph without replenishing the kleptoplasts; or 2) it behaves as a mixotroph (photoautotroph and herbivorous consumer) and replenishes kleptoplasts continually or periodically. To address the question of which hypothesis is more likely, we examined the source algae for kleptoplasts and temporal changes in kleptoplast composition and nutritional contribution. By characterizing the temporal diversity of P. ocellatus kleptoplasts using rbcL sequences, we found that P. ocellatus harvests kleptoplasts from at least 8 different siphonous green algal species, that kleptoplasts from more than one species are present in each individual sea slug, and that the kleptoplast composition differs temporally. These results suggest that wild P. ocellatus often feed on multiple species of siphonous algae from which they continually obtain fresh chloroplasts. By estimating the trophic position of wild and starved P. ocellatus using the stable nitrogen isotopic composition of amino acids, we showed that despite the abundance of kleptoplasts, their photosynthates do not contribute greatly to the nutrition of wild P. ocellatus, but that kleptoplast photosynthates form a significant source of nutrition for starved sea slugs. The herbivorous nature of wild P. ocellatus is consistent with insights from molecular analyses indicating that kleptoplasts are frequently replenished from ingested algae, leading to the conclusion that natural populations of P. ocellatus do not rely on photosynthesis but mainly on the digestion of ingested algae.


Architectural protein subclasses shape 3D organization of genomes during lineage commitment.
Understanding the topological configurations of chromatin may reveal valuable insights into how the genome and epigenome act in concert to control cell fate during development. Here, we generate high-resolution architecture maps across seven genomic loci in embryonic stem cells and neural progenitor cells. We observe a hierarchy of 3D interactions that undergo marked reorganization at the submegabase scale during differentiation. Distinct combinations of CCCTC-binding factor (CTCF), Mediator, and cohesin show widespread enrichment in chromatin interactions at different length scales. CTCF/cohesin anchor long-range constitutive interactions that might form the topological basis for invariant subdomains. Conversely, Mediator/cohesin bridge short-range enhancer-promoter interactions within and between larger subdomains. Knockdown of Smc1 or Med12 in embryonic stem cells results in disruption of spatial architecture and downregulation of genes found in cohesin-mediated interactions. We conclude that cell-type-specific chromatin organization occurs at the submegabase scale and that architectural proteins shape the genome in hierarchical length scales.


Statin Therapy and Risk of Polyneuropathy in Type 2 Diabetes: A Danish Cohort Study.
Statins may reduce the risk of diabetic polyneuropathy (DPN) as a result of lipid-lowering and anti-inflammatory effects, but statins have also been associated with neurotoxicity. We examined whether statin therapy affects the risk of DPN. We identified all Danish patients with incident type 2 diabetes during 2002-2016. New users initiated statins between 180 days before and 180 days after their first diabetes record, while prevalent users had initiated statins before that period. Patients were followed for incident DPN using validated hospital diagnosis codes, starting 180 days after their first diabetes record. Cox proportional hazard analysis was used to compute adjusted hazard ratios (aHRs) for DPN. The study cohort comprised 59,255 (23%) new users, 75,528 (29%) prevalent users, and 124,842 (48%) nonusers; median follow-up time was 6.2 years (interquartile range 3.4-9.6). The incidence rate of DPN events per 1,000 person-years was similar in new users (4.0 [95% CI 3.8-4.2]), prevalent users (3.8 [3.6-3.9]), and nonusers (3.8 [3.7-4.0]). The aHR for DPN was 1.05 (0.98-1.11) in new users and 0.97 (0.91-1.04) in prevalent users compared with statin nonusers. New users had a slightly increased DPN risk during the first year (1.31 [1.12-1.53]), which vanished after >2 years of follow-up. Findings were similar in on-treatment and propensity score-matched analyses and with additional adjustment for pretreatment blood lipid levels. Statin therapy is unlikely to increase or mitigate DPN risk in patients with type 2 diabetes, although a small acute risk of harm cannot be excluded.


Stochastic dynamics of a finite-size spiking neural network.
We present a simple Markov model of spiking neural dynamics that can be analytically solved to characterize the stochastic dynamics of a finite-size spiking neural network. We give closed-form estimates for the equilibrium distribution, mean rate, variance, and autocorrelation function of the network activity. The model is applicable to any network where the probability of firing of a neuron in the network depends on only the number of neurons that fired in a previous temporal epoch. Networks with statistically homogeneous connectivity and membrane and synaptic time constants that are not excessively long could satisfy these conditions. Our model completely accounts for the size of the network and correlations in the firing activity. It also allows us to examine how the network dynamics can deviate from mean field theory. We show that the model and solutions are applicable to spiking neural networks in biophysically plausible parameter regimes.


Plasma carotenoids, vitamin C, tocopherols, and retinol and the risk of breast cancer in the European Prospective Investigation into Cancer and Nutrition cohort.
Carotenoids and vitamin C are thought to be associated with reduced cancer risk because of their antioxidative capacity. This study evaluated the associations of plasma carotenoid, retinol, tocopherol, and vitamin C concentrations and risk of breast cancer. In a nested case-control study within the European Prospective Investigation into Cancer and Nutrition cohort, 1502 female incident breast cancer cases were included, with an oversampling of premenopausal (n = 582) and estrogen receptor-negative (ER-) cases (n = 462). Controls (n = 1502) were individually matched to cases by using incidence density sampling. Prediagnostic samples were analyzed for α-carotene, β-carotene, lycopene, lutein, zeaxanthin, β-cryptoxanthin, retinol, α-tocopherol, γ-tocopherol, and vitamin C. Breast cancer risk was computed according to hormone receptor status and age at diagnosis (proxy for menopausal status) by using conditional logistic regression and was further stratified by smoking status, alcohol consumption, and body mass index (BMI). All statistical tests were 2-sided. In quintile 5 compared with quintile 1, α-carotene (OR: 0.61; 95% CI: 0.39, 0.98) and β-carotene (OR: 0.41; 95% CI: 0.26, 0.65) were inversely associated with risk of ER- breast tumors. The other analytes were not statistically associated with ER- breast cancer. For estrogen receptor-positive (ER+) tumors, no statistically significant associations were found. The test for heterogeneity between ER- and ER+ tumors was statistically significant only for β-carotene (P-heterogeneity = 0.03). A higher risk of breast cancer was found for retinol in relation to ER-/progesterone receptor-negative tumors (OR: 2.37; 95% CI: 1.20, 4.67; P-heterogeneity with ER+/progesterone receptor positive = 0.06). We observed no statistically significant interaction between smoking, alcohol, or BMI and all investigated plasma analytes (based on tertile distribution). Our results indicate that higher concentrations of plasma β-carotene and α-carotene are associated with lower breast cancer risk of ER- tumors.


Optimising child outcomes from parenting interventions: fathers' experiences, preferences and barriers to participation.
Early childhood interventions can have both immediate and long-term positive effects on cognitive, behavioural, health and education outcomes. Fathers are underrepresented in interventions focusing on the well-being of children. However, father participation may be critical for intervention effectiveness, especially for parenting interventions for child externalising problems. To date, there has been very little research conducted to understand the low rates of father participation and to facilitate the development of interventions to meet the needs of fathers. This study examined fathers' experiences of, and preferences for, parenting interventions as well as perceptions of barriers to participation. It also examined how these factors were associated with child externalising behaviour problems, and explored the predictors of participation in parenting interventions. A community sample of 1001 fathers of children aged 2-16 years completed an online survey about experiences with parenting interventions, perceived barriers to participation, the importance of different factors in their decision to attend, and preferred content and delivery methods. They also completed ratings of their child's behaviour using the Strengths and Difficulties Questionnaire. Overall, 15% of fathers had participated in a parenting intervention or treatment for child behaviour, with significantly higher rates of participation for fathers of children with high versus low levels of externalising problems. Fathers rated understanding what is involved in the program and knowing that the facilitator is trained as the two most important factors in their decision to participate. There were several barriers to participation that fathers of children with high-level externalising problems were more likely to endorse, across practical barriers and help-seeking attitudes, compared to fathers of children with low-level externalising problems. Almost two-thirds of fathers of children with high-level externalising behaviour had not participated in a parenting intervention or treatment. The only significant predictors of intervention participation were severity of child externalising behaviour problems and child age. The findings have important implications for services seeking to increase father engagement and highlight a number of strategies to enhance the promotion and delivery of parenting interventions to fathers. These strategies include more public health messaging about parenting programs and the importance of father participation.


Anaesthetic considerations for the child with leukodystrophy.
The author presents a four-year-old boy with Pelizaeus-Merzbacher disease who required anaesthesia during placement of PE (pressure equalization) tubes and a permanent silastic intravascular device (Broviac catheter). Pelizaeus-Merzbacher is one of a group of progressive, degenerative disorders of the cerebral white matter known as the leukodystrophies. They include metachromatic leukodystrophy, adrenoleukodystrophy, Krabbe's disease, Canavan's disease, Alexander's disease and Pelizaeus-Merzbacher disease. Due to the progressive nature of the disorders and their devastating effects on the central nervous system, these children frequently require anaesthesia during imaging procedures such as MRI or during various surgical procedures. Of concern to the anaesthetist is the high prevalence of seizure disorders, gastroesophageal reflux with the risk of aspiration, and airway complications related to poor pharyngeal muscle control and copious oral secretions. In addition, adrenal involvement and hypofunction may be seen in patients with adrenoleukodystrophy. Identification of these associated conditions during the preoperative examination will allow safe anaesthesia for these children.


Use of a monoclonal antibody in an enzyme immunoassay for the detection of Entamoeba histolytica in fecal specimens.
An indirect enzyme-linked immunosorbent assay (ELISA) was developed for the detection of Entamoeba histolytica in human feces, using both a monoclonal antibody and rabbit antisera. It detected from less than 1 to 57 trophozoites of 6 E. histolytica strains. Stool specimens were positive by ELISA in 18 of 22 (82%) patients with E. histolytica and in 3 of 186 (2%) of patients without demonstrable E. histolytica in their stools. The latter included one from a child living near an asymptomatic cyst carrier and another from a traveler with giardiasis who had recently taken antibiotics. One hundred eight of 183 microscopy-and ELISA-negative specimens contained other parasites including Giardia (49 specimens), Endolimax nana (24), Entamoeba coli (21), Iodamoeba butschlii (2), and Entamoeba hartmanni (1). This ELISA for E. histolytica is a simple, sensitive and specific diagnostic tool.


Are group-based and individual physiotherapy exercise programmes equally effective for musculoskeletal conditions? A systematic review and meta-analysis.
Musculoskeletal pain is common and its treatment costly. Both group and individual physiotherapy interventions which incorporate exercise aim to reduce pain and disability. Do the additional time and costs of individual physiotherapy result in superior outcomes? To compare the effectiveness of group and individual physiotherapy including exercise on musculoskeletal pain and disability. Eleven electronic databases were searched by two independent reviewers. Randomised controlled trials (RCTs) including participants with musculoskeletal conditions which compared group and individual physiotherapy interventions that incorporated exercise were eligible. Study quality was assessed using the PEDro scale by two independent reviewers, and treatment effects were compared by meta-analyses. Fourteen RCTs were eligible, including patients with low back pain (7 studies), neck pain (4), knee pain (2) and shoulder pain (1). We found no clinically significant differences in pain and disability between group and individual physiotherapy involving exercise. Only small, clinically irrelevant differences in pain or disability outcomes were found between group and individual physiotherapy incorporating exercise. Since all but one study included other interventions together with exercise in either the group or individual arm, deciphering the unique effect of the way in which exercise is delivered is difficult. Group interventions may need to be considered more often, given their similar effectiveness and potentially lower healthcare costs.