The CB(1) cannabinoid receptor drives corticospinal motor neuron differentiation through the Ctip2/Satb2 transcriptional regulation axis.
The generation and specification of pyramidal neuron subpopulations during development relies on a complex network of transcription factors. The CB(1) cannabinoid receptor is the major molecular target of endocannabinoids and marijuana active compounds. This receptor has been shown to influence neural progenitor proliferation and axonal growth, but its involvement in neuronal differentiation and the functional impact in the adulthood caused by altering its signaling during brain development are not known. Here we show that the CB(1) receptor, by preventing Satb2 (special AT-rich binding protein 2)-mediated repression, increased Ctip2 (COUP-TF interacting protein 2) promoter activity, and Ctip2-positive neuron generation. Unbalanced neurogenic fate determination found in complete CB(1)(-/-) mice and in glutamatergic neuron-specific Nex-CB(1)(-/-) mice induced overt alterations in corticospinal motor neuron generation and subcerebral connectivity, thereby resulting in an impairment of skilled motor function in adult mice. Likewise, genetic deletion of CB(1) receptors in Thy1-YFP-H mice elicited alterations in corticospinal tract development. Altogether, these data demonstrate that the CB(1) receptor contributes to the generation of deep-layer cortical neurons by coupling endocannabinoid signals from the neurogenic niche to the intrinsic proneurogenic Ctip2/Satb2 axis, thus influencing appropriate subcerebral projection neuron specification and corticospinal motor function in the adulthood.


Comparison of player movement patterns between 1-day and test cricket.
Physical demands of cricket presumably vary by both game format and performance level. Differences in player movement patterns between 2 game formats (1 day and multiday) and 2 levels of elite performance (state and international) were quantified with global positioning system technology. Five movement categories were established, and 15 movement pattern variables were reported. Data from state (n = 42, 200 files) and international (n = 12, 63 files) cricketers were scaled to hourly values to compare movement demands. Cricketers generally covered similar distances in both formats, except for state 1-day fielders who covered moderately greater distance (~0.7 km·h⁻¹ more; 21 ± 8%; mean ± 90% confidence interval) than state multiday (first-class) fielders. State 1-day cricketers also covered small to moderately greater distances (running 41 ± 13%; striding 38 ± 16%; sprinting 39 ± 36%) in the faster movement patterns and consequently had moderately less recovery time (13-67%) between high-intensity efforts as first-class cricketers. Comparisons of movements between performance levels revealed similar total distances between state and international cricketers. However, Test fielders covered moderately greater (29-48%) distances at the higher-intensity movement patterns (running, striding, and sprinting) than first-class fielders. In summary, although movement patterns were broadly similar between formats and levels, it appears that one day cricket (compared with multiday games) and test matches (compared with state-level competition) require more higher-intensity running. Conditioning coaches should train state and international 1-day cricket players similarly, but should account for the higher physical demands of international multiday cricket.


An effective oxidation route to blue emission CdSe quantum dots.
Nearly monodisperse CdSe quantum dots with blue emission are obtained through an oxidation approach, in which CdSe particles can be etched into smaller ones. During the oxidation process, CdSe with yellow emission (546 nm) can be rapidly oxidized to blue emission (466 nm) due to its incompletely crystallized structure. Further oxidation results in the slow blue-shift of the photoluminescence peak to 433nm. The quantum fluorescence efficiency of CdSe with blue emission is about 10%, and surface-trap emission becomes evident when the PL peak of CdSe reaches the blue-violet region, since the surface atom ratio increases. This oxidation route offers a simple and mild way to get extremely small CdSe quantum dots.


Resource utilization and use of life-extending therapies and corticosteroids in prostate cancer patients with corticosteroid-sensitive comorbidities.
Corticosteroids (CSs) are used concomitantly with life-extending therapies (LETs) in patients with castration-resistant prostate cancer (CRPC). This study examined time to LETs, LETs and concomitant CS adherence, and monthly all-cause healthcare utilization and costs in patients with CPRC with and without CS-sensitive comorbidities in the Veterans Health Administration population. Patients had CRPC if records showed prostate cancer diagnosis, medical/surgical castration and ≥2 prostate-specific antigen increases through 1 June 2007-31 May 2012. CS-sensitive comorbidities were assessed 6 months prior to the index date. Adherence, defined as medication possession ratio (MPR) ≥0.8, among patients initiating LETs (cabazitaxel, docetaxel, or abiraterone acetate) before 30 November 2011, resource utilization and costs among patients with concomitant CS were assessed. Statistical analysis included descriptive, Cox proportional hazards, and logistic regression models. Common CS-sensitive conditions among 12,128 patients with CRPC included hypertension (75.74%) and hyperlipidemia (54.69%). Those with glaucoma (hazard ratio [HR] = 0.67), ischemic heart disease (HR = 0.78), and peripheral vascular disease (PVD) (HR = 0.78) were less likely to be prescribed LETs (all p < 0.01). Duration of LET was shorter among patients with CS-sensitive comorbidities (125.02 vs 133.08 days; p = 0.04) in the 6 month follow-up period. Among LET-treated patients with and without CS-sensitive comorbidities, less than half had MPR ≥ 0.8 (LET: 48.72% vs 54.05%; concomitant CS: 42.19% vs 40.54%, respectively). Cerebrovascular disease (odds ratio = 0.107; 95% confidence interval = 0.012 to 0.966) and PVD (odds ratio = 0.523; 95% confidence interval = 0.276 to 0.991) were associated with reduced CS adherence. Among patients with concomitant CS, those with CS-sensitive comorbidities had more inpatient stays than those without (20.45% vs 12.88%; p = 0.033), incurring higher monthly inpatient costs ($1157 vs $342; p < 0.0001) and total costs ($5725 vs $4772; p = 0.036). CS-sensitive conditions influence initiation and duration of LETs, concomitant CS adherence, inpatient stays, and total costs. Future efforts should focus on specific strategies for treating prostate cancer patients with CS-sensitive comorbidities to ensure that they have appropriate access to LETs and to reduce costs and inpatient stays. Study limitations include the use of retrospective claims data and the relatively restricted subpopulation of older North American males.


Versatile inhibitory effects of the flavonoid-derived PI3K/Akt inhibitor, LY294002, on ATP-binding cassette transporters that characterize stem cells.
Stem cells are undifferentiated cells capable of proliferation, self-renewal, and production of a large number of differentiated progeny. Stem cells exist even in malignancies. They are called cancer stem cells, which may represent the origin of these tumors and may be one of the reasons of chemoresistance. The phosphatidylinositol-3-kinase (PI3K)/Akt pathway is important for the maintenance of pluripotency in stem cells. Flow cytometry assay for identifying stem cells defines a side population of cells that displays low fluorescent dye and is highly enriched for stem cells. The dye efflux is attributed to expression of ATP-binding cassette transporters such as P-glycoprotein and breast cancer resistance protein (BCRP)/ABCG2, which also transport a variety of anticancer drugs. The PI3K/Akt pathway can modulate functions of ABC transporters through various mechanisms. Reportedly, inhibition of the PI3K/Akt pathway caused BCRP translocation in hematopoietic stem cells and glioma stem-like cells. On the other hand, a PI3K inhibitor, LY294002, reversed multidrug resistance in cancer cells that overexpress BCRP not by affecting BCRP translocation but putatively as a competitive inhibitor. Other PI3K inhibitors, wortmannin and PI-103, did not reverse BCRP-mediated drug resistance. Since LY294002 is a derivative of quercetin that is a naturally occurring flavonoid, its chemical structure is similar to those of a group of flavonoids but those of wortmannin and PI-103 are quite different. It is known that many flavonoids are inhibitors of BCRP and PI3K. LY294002 has also been reported to exert inhibitory effects on multidrug resistance-associated protein 1 (MRP1) function via dual mechanisms, competitive block of substrate transport and modulation of expression. Furthermore, LY294002 has been found to antagonize transport activity of P-glycoprotein without influencing its expression. Taken together, LY294002 can inhibit all BCRP, P-glycoprotein, and MRP1, which are three major ABC transporters that are highly expressed in stem cells and cause multidrug resistance. Due to its versatile effects, LY294002 could be a lead compound for developing more effective and tolerable reagents for cancer treatment.


Use of advance directives for high-risk operations: a national survey of surgeons.
To characterize surgeons' beliefs and approach to the use of an advance directive in the decision to perform high-risk operations. Prior work suggests many surgeons regard advance directives as antithetical to the goals of surgical therapy, yet little is known about surgeons' approach to high-risk operations for patients with directives limiting postoperative care. We sent a self-administered survey by US mail to 2100 randomly selected vascular, neurologic, and cardiothoracic surgeons. We used stepwise logistic regression to determine the relationship between explanatory variables and: (1) how often surgeons discuss advance directives preoperatively, and (2) how advance directives limiting postoperative life-supporting therapy influence the decision to operate. The adjusted response rate was 55%. All surgeons reported discussing the potential for unanticipated outcomes and nearly all (95%) discussed the need for postoperative life-supporting therapy. More than four-fifths (81%) reported discussing patient preferences to limit postoperative life-supporting therapy during informed consent. Approximately one half of respondents (52%) either sometimes or always discuss advance directives before surgery, with younger physicians less likely to do so than more experienced surgeons (odds ratio [OR] = 0.46, 95% confidence intervals [CI] = 0.06-0.85). More than one half (54%) of surgeons reported they would decline to operate on patients who have an advance directive limiting postoperative life-supporting therapy. Many surgeons do not routinely discuss advanced directives preoperatively and more than one half reported they would decline to operate on patients whose directives limit postoperative care. This practice may limit the expression of patient preferences during decision making for high-risk operations.


Mesochronal Structure Learning.
Standard time series structure learning algorithms assume that the measurement timescale is approximately the same as the timescale of the underlying (causal) system. In many scientific contexts, however, this assumption is violated: the measurement timescale can be substantially slower than the system timescale (so intermediate time series datapoints will be missing). This assumption violation can lead to significant learning errors. In this paper, we provide a novel learning algorithm to extract system-timescale structure from measurement data that undersample the underlying system. We employ multiple algorithmic optimizations that exploit the problem structure in order to achieve computational tractability. The resulting algorithm is highly reliable at extracting system-timescale structure from undersampled data.


Visual search in typically developing toddlers and toddlers with Fragile X or Williams syndrome.
Visual selective attention is the ability to attend to relevant visual information and ignore irrelevant stimuli. Little is known about its typical and atypical development in early childhood Experiment 1 investigates typically developing toddlers' visual search for multiple targets on a touch-screen. Time to hit a target, distance between successively touched items, accuracy and error types revealed changes in 2- and 3-year-olds' vulnerability to manipulations of the search display. Experiment 2 examined search performance by toddlers with Fragile X syndrome (FXS) or Williams syndrome (WS). Both of these groups produced equivalent mean time and distance per touch as typically developing toddlers matched by chronological or mental age; but both produced a larger number of errors. Toddlers with WS confused distractors with targets more than the other groups; while toddlers with FXS perseverated on previously found targets. These findings provide information on how visual search typically develops in toddlers, and reveal distinct search deficits for atypically developing toddlers.


Patient Support Program Increased Medication Adherence with Lower Total Health Care Costs Despite Increased Drug Spending.
The U.S. health care system is currently evolving from a volume-based care to a value-based care approach, which is in part supported by the introduction of patient support programs (PSP). For patients treated with adalimumab (ADA), the addition of a dedicated, trained nurse to the PSP (HUMIRA Complete, rolled out nationally in 2015) provides further emphasis on value-based care. To determine the effectiveness of the HUMIRA Complete PSP, including the Nurse Ambassador component, in a real-world setting for patients receiving ADA across a broad range of approved indications (rheumatoid arthritis, Crohn's disease, ulcerative colitis, psoriasis, psoriatic arthritis, ankylosing spondylitis, uveitis, and hidradenitis suppurativa). A longitudinal retrospective study was conducted using patient-level data from the HUMIRA Complete PSP data linked to the real-world, patient-level Symphony Health Solutions administrative claims database. Commercially insured patients were included who were aged ≥ 18 years with ≥ 2 diagnoses of an indicated disease who were biologically naive before initiating ADA or who had no claims for synthetic-targeted immune modulator therapy before their earliest ADA claim in the database between January 2015 and February 2017. The first claim had to have occurred in 2015 or later, and continuous medical and drug data coverage were required for ≥ 6 months before and ≥ 12 months after the first ADA claim and index date. PSP patients (with at least an initial and follow-up dedicated nurse call) were matched 1:1 to non-PSP patients based on pharmacy type, indication, and propensity score, estimated with covariates for age, sex, year of first ADA use, and baseline comorbidities. Adherence to ADA was compared using proportion of days covered along with discontinuation of ADA, defined as a gap in treatment greater than the previous days supply with no additional ADA claim, total costs, medical costs, and drug costs (2017 U.S. dollars) over 12 months. Baseline demographic and clinical characteristics were summarized descriptively. Differences between cohorts were assessed using t-tests for adherence and costs and log-rank tests for discontinuation. 2,268 patients (1,134 per group) were included. Baseline characteristics were similar between cohorts after matching. Participation in the PSP was associated with 29.3% higher ADA adherence (64.8% vs. 50.1%; P < 0.0001) and 22.0% lower ADA discontinuation rate (51.4% vs. 65.9%; P < 0.0001). Disease-related medical costs and all-cause medical costs were significantly lower by 35% ($10,162 vs. $15,511; P = 0.005) and 29.2% ($25,074 vs. $35,419; P = 0.0004), respectively, for PSP versus non-PSP patients. Total costs were also lower by 9% ($62,421 vs. $68,706; P = 0.056), and drug costs were 12.2% higher ($37,347 vs. $33,287; P = 0.0016). This retrospective study demonstrates that participation in the PSP augments value-based care by improving outcomes for patients with chronic diseases by helping them not only manage a complex treatment regimen but also lower annual health care costs. Design, study conduct, and financial support for this study were provided by AbbVie. AbbVie participated in the interpretation of data, review, and approval of the manuscript; all authors contributed to the development of the publication and maintained control over the final content. Brixner reports consulting fees from AbbVie, AstraZeneca, Becton Dickinson, Millcreek Outcomes Group, Sanofi, and UCB Pharma. Rubin reports consulting fees from AbbVie, Abgenomics, Allergan, Forward Pharma, Genentech/Roche, Janssen Pharmaceuticals, Merck & Co., Napo Pharmaceuticals, Pfizer, Shire, Takeda, and Target Pharmaceuticals and research support from AbbVie, Genentech/Roche, Janssen Pharmaceuticals, Prometheus Laboratories, Shire, and Takeda. Mease reports grant/research support from AbbVie, Amgen, BMS, Celgene, Genentech, Janssen, Lilly, Merck, Novartis, Pfizer, SUN Pharma, and UCB; consulting fees from AbbVie, Amgen, BMS, Celgene, Genentech, Janssen, Lilly, Merck, Novartis, Pfizer, SUN Pharma, and UCB; and served on the speakers bureaus for AbbVie, Amgen, BMS, Celgene, Genentech, Janssen, Lilly, Merck, Novartis, Pfizer, Roche, and UCB. Mittal and Ganguli are employees and stockholders of AbbVie. Liu has no financial conflict of interest. Davis is an employee of Medicus Economics, which reports payment from AbbVie to participate in this research. Fendrick reports personal fees from Merck, AstraZeneca, Trizetto, Amgen, Lilly, AbbVie, Johnson & Johnson, and Sanofi; grants from the National Pharmaceutical Council, PhRMA, the Gary and Mary West Health Foundation, the states of New York and Michigan, the Laura and John Arnold Foundation, the Robert Wood Johnson Foundation, and the Agency for Healthcare Research and Quality; and has equity in Zansors, Sempre Health, Wellth, and V-BID Health. Data from this study were presented in part at the Academy of Managed Care & Specialty Pharmacy Annual Meeting; April 25, 2018; Boston, MA.


Evaluation of optical coherence tomography angiographic findings in Alzheimer's type dementia.
To identify the retinal vascular pathologies in patients with Alzheimer's type dementia (ATD) through optical coherence tomography angiography (OCTA) imaging. Our study included 26 patients in the patient group, and age-matched and sex-matched 26 subjects in the control group. A detailed ophthalmological and neurological examination was performed for all subjects included in the study. The retinal, choroidal vascular structures and choroidal thickness (CT) of all subjects were analysed in a detailed way with a commercial spectral domain OCTA. Moreover, all participants underwent detailed neurological examination including Mini Mental State Examination (MMSE) test to evaluate cognitive function. In the group of patients with ATD, the MMSE score was significantly lower than that of the control group (p<0.001). The retinal vascular density was significantly lower than that of the control group in all zones (p<0.05). Foveal avascular zone (FAZ) was significantly enlarged compared with the control group (p=0.001). CT was significantly lower in the group of patients with ATD (p<0.001). Outer retinal and choroidal flow rates were lower in the group of patients with ATD, while the difference was not significant (p>0.05). Furthermore, significant correlation was found between the MMSE and all vascular density parameters, CT parameter and FAZ tested with OCTA imaging (p<0.05). In patients with ATD, retinal and choroidal vascular pathologies detected through OCTA imaging can be used as a new biomarker in the early diagnosis of the disease, follow-up of its progression and in investigating the efficacy of the drugs.


[Oxytocin in cesarean sections: what is the best way to use it?].
Oxytocin is the uterotonic used in obstetric anesthesia, and its prophylactic and therapeutic administration is justified because it reduces the incidence of post-partum hemorrhage. However, the ideal infusion regimen in elective cesarean sections has not been determined yet. The objective of this study was to review the main physiological and pharmacological characteristics of oxytocin and to discuss its rational use by anesthesiologists in view of its side effects. Oxytocin is produced by the hypothalamus and stored in the posterior lobe of the pituitary gland. In the uterus, is causes contraction of the smooth muscle, which is very important to control hemorrhage after uterine emptying. It also affects other systems, and the reduction in peripheral vascular resistance with consequent hypotension is very important. The extra-uterine actions of oxytocin are important when administered in high doses or in bolus, especially in parturients under anesthesia (spinal block or general anesthesia) with hypovolemia or preexistent alterations in the cardiovascular system. Several infusion regimens have been studied, varying the dose and/or the speed of administration, in an attempt to establish the most adequate. Due to its wide therapeutic spectrum, oxytocin remains the drug of choice to prevent uterine atony after cesarean sections. Although it has been used for almost 50 years, the adequate infusion regimen in cesarean sections has not been determined yet. The current tendency is to use continual infusion of low doses, and bolus administration should be avoided.


Identification of methicillin-resistant strains of staphylococci by polymerase chain reaction.
A simple and reliable method using a polymerase chain reaction (PCR) was devised to identify methicillin-resistant staphylococci. By using lysates of the strain to be tested as templates and 22-mer oligonucleotides as primers, a 533-bp region of mecA, the structural gene of a low-affinity penicillin-binding protein (PBP 2'), was amplified by PCR and detected by agarose gel electrophoresis. Results obtained by this method were compared with those obtained by broth microdilution MIC determination for 210 and 100 clinical isolates of Staphylococcus aureus and coagulase-negative staphylococci, respectively. Of 99 mecA-negative S. aureus isolates, 100% of the strains were methicillin susceptible and 98% of the strains were oxacillin susceptible. Three strains (3%) of 111 mecA-positive S. aureus isolates exhibited almost the same susceptibility to beta-lactams as the mecA-negative ones and did not produce detectable amounts of PBP 2' despite the presence of the mecA gene. One of them yielded typically methicillin-resistant variants at a low frequency with concomitant recovery of PBP 2' production. The mecA gene was also found in coagulase-negative Staphylococcus epidermidis, Staphylococcus haemolyticus, Staphylococcus sciuri, Staphylococcus saprophyticus, and Staphylococcus caprae and conferred resistance on most of the bacteria.


Steroids in leprosy type 1 (reversal) reactions: mechanisms of action and effectiveness.
Steroids are widely used for the treatment of leprosy reactions. The effectiveness of steroid treatment is variable, with only 60% of patients regaining nerve function. Sequential skin biopsy specimens, obtained from 15 patients with type 1 (reversal) reactions, have been studied to document the cytokine profile and cellularity of the lesions. All of the patients were placed on a standard course of steroids after the first biopsy. Subsequent biopsies were performed seven, 28 and 180 days later. The specimens were stained for interferon-gamma (IFN gamma), interleukin-12 (IL-12) and inducible nitric oxide synthase (iNOS). After the first biopsy, all patients were placed on a standard reducing course of steroids beginning at 30 mg daily. By day 7, treatment with prednisolone showed little effect on the cellularity and cytokine profiles. However, by day 28, significant decreases of IFN-gamma, IL-12 and iNOS were found for most patients. Some patients maintained cytokine production at day 28 and even at day 180. These data illustrate the strong Th1 profile of type 1 reactional lesions, the relatively slow response to therapy, and the continuing activity after treatment with steroids for 180 days. The variation of individual responses emphasizes their importance. Additional prospective studies will be required to determine whether patients with high intra-lesional levels of cytokine are at risk of recurrent reactions. The need for studies both of different glucocorticoids and of other non-steroidal immunosuppressants for the treatment of reactions is discussed.


Trends in smoking and lung cancer mortality in Switzerland.
Patterns of cigarette smoking in Switzerland were analyzed on the basis of sales data (available since 1924) and national health surveys conducted in the last decade. There was a steady and substantial increase in cigarettes sales up to the early 1970s. Thereafter, the curve tended to level off around an average value of 3,000 cigarettes per adult per year. According to the 1981-1983 National Health Survey, 37% of Swiss men were current smokers, 25% were ex-smokers, and 39% were never smokers. Corresponding porportions in women were 22, 11, and 67%. Among men, smoking prevalence was higher in lower social classes, and some moderate decline was apparent from survey data over the period 1975-1981 mostly in later middle-age. Trends in lung cancer death certification rates over the period 1950-1984 were analyzed using standard cross-sectional methods and a log-linear Poisson model to isolate the effects of age, birth cohort, and year of death. Mortality from lung cancer increased substantially among Swiss men between the early 1950s and the late 1970s, and levelled off (around a value of 70/100,000 men) thereafter. Among women, there has been a steady upward trend which started in the mid-1960s, and continues to climb steadily, although lung cancer mortality is still considerably lower in absolute terms (around 8/100,000 women) than in several North European countries or in North America. Cohort analyses indicate that the peak rates in men were reached by the generation born around 1910 and mortality stabilized for subsequent generations up to the 1930 birth cohort. Among females, marked increases were observed in each subsequent birth cohort. This pattern of trends is consistent with available information on smoking prevalence in successive generations, showing a peak among men for the 1910 cohort, but steady upward trends among females. Over the period 1980-1984, about 90% of lung cancer deaths among Swiss men and about 40% of those among women could be attributed to smoking (overall proportion, 85%).


N-butyldeoxygalactonojirimycin: a more selective inhibitor of glycosphingolipid biosynthesis than N-butyldeoxynojirimycin, in vitro and in vivo.
N-Butyldeoxynojirimycin (NB-DNJ) inhibits the ceramide glucosyltransferase which catalyses the first step in glycosphingolipid (GSL) biosynthesis. It has the potential to be used for the treatment of the GSL lysosomal storage diseases and is currently in clinical trials for the treatment of type 1 Gaucher's disease. However, NB-DNJ is also a potent inhibitor of other enzymes, including alpha-glucosidase I and II, which could potentially cause side effects in patients receiving life-long therapy. Wetherefore evaluated a potentially more selective GSL biosynthesis inhibitor, N-butyldeoxygalactonojirimycin (NB-DGJ), in vitro and in vivo. The distribution and degree of GSL depletion in the liver of mice treated with NB-DGJ or NB-DNJ were equivalent. Mice treated with NB-DGJ had normal body weights and lymphoid organ sizes, whereas NB-DNJ-treated mice showed weight loss and partial lymphoid organ shrinkage. NB-DNJ inhibited glycogen catabolism in the liver, whereas NB-DGJ did not. NB-DNJ was also a potent inhibitor of sucrase and maltase in vitro but not of lactase, while NB-DGJ inhibited lactase but not sucrase or maltase. NB-DGJ is therefore more selective than NB-DNJ, and deserves to be evaluated for human therapy.


Understanding enrolment in community health insurance in sub-Saharan Africa: a population-based case-control study in rural Burkina Faso.
To identify factors associated with decision to enrol in a community health insurance (CHI) scheme. We conducted a population-based case-control study among 15 communities offered insurance in 2004 in rural Burkina Faso. For inclusion in the study, we selected all 154 enrolled (cases) and a random sample of 393 non-enrolled (controls) households. We used unconditional logistic regression (applying Huber-White correction to account for clustering at the community level) to explore the association between enrolment status and a set of household head, household and community characteristics. Multivariate analysis revealed that enrolment in CHI was associated with Bwaba ethnicity, higher education, higher socioeconomic status, a negative perception of the adequacy of traditional care, a higher proportion of children living within the household, greater distance from the health facility, and a lower level of socioeconomic inequality within the community, but not with household health status or previous household health service utilization. Our study provides evidence that the decision to enrol in CHI is shaped by a combination of household head, household, and community factors. Policies aimed at enhancing enrolment ought to act at all three levels. On the basis of our findings, we discuss specific policy recommendations and highlight areas for further research.


The anti-oxidant effects of ginger and cinnamon on spermatogenesis dys-function of diabetes rats.
Diabetes rats have been linked to reproductive dysfunction and plant medicine has been shown to be effective in its treatment. Antioxidants have distinctive effects on spermatogenesis, sperm biology and oxidative stress, and changes in anti-oxidant capacity are considered to be involved in the pathogenesis of chronic diabetes mellitus. Ginger and cinnamon are strong anti-oxidants and have been shown to reduce oxidative stress in the long-term treatment of streptozotocin (STZ)-induced diabetes in animal models. The present study examined the influence of combined ginger and cinnamon on spermatogenesis in STZ-induced diabetes in male Wistar rats. Animals (n = 80) were allocated randomly into eight groups, 10 each: Group 1: Control rats given only 5cc Normal saline (0.9% NaCl) daily;Group2: rats received ginger (100mg/kg/rat) daily; Group 3: rats received cinnamon (75mg/kg) daily; Group 4: rats received ginger and cinnamon, (100mg/kg/rat ginger and 75mg/kg cinnamon) daily; Group 5: Diabetic control rats received only normal saline. Group 6: Diabetic rats received 100mg/kg/day ginger; Group 7: Diabetic rats received 75mg /kg/ day cinnamon; Group 8: Diabetic rats received ginger and cinnamon (100mg/kg/day and 75mg/kg /day). Diabetes was induced with 55 mg/kg, single intra-peritoneal injection of STZ in all groups. At the end of the experiment (56th day), blood samples were taken for determination of testosterone, LH,FSH, total anti-oxidant capacity, and levels of malondialdehyde, SOD, Catalase and GPX. All rats were euthanized, testes were dissected out and spermatozoa were collected from the epididymis for analysis. Sperm numbers, percentages of sperm viability and motility, and total serum testosterone increased in ginger and cinnamon and combined ginger and cinnamon treated diabetic rats compared with control groups. Serum testosterone, LH and FSH were higher compared to control group and also serum anti-oxidants (TAC, SOD, GPX and catalase) all were increased at the end of treatment. Combined ginger and cinnamon showed more intense increase in all parameters compare to ginger and cinnamon alone. Most of the results were significant (P<0.05). We concluded that combined ginger and cinnamon have significant beneficial effects on the sperm viability, motility, and serum total testosterone, LH,FSH and serum anti-oxidants' level and could be effective for maintaining healthy sperm parameters and male reproductive function in diabetics.


Diabetic retinopathy: new therapeutic perspectives based on pathogenic mechanisms.
Diabetic retinopathy (DR) is the leading cause of visual impairment and preventable blindness and represents a significant socioeconomic cost for healthcare systems worldwide. In early stages of DR the only therapeutic strategy that physicians can offer is a tight control of the risk factors for DR (mainly blood glucose and blood pressure). The currently available treatments for DR are applicable only at advanced stages of the disease and are associated with significant adverse effects. Therefore, new treatments for the early stages of DR are needed. However, in early stages of DR invasive treatments such as intravitreal injections are too aggressive, and topical treatment seems to be an emerging route. In the present review, therapeutic strategies based on the main pathogenic mechanisms involved in the development of DR are reviewed. The main gap in the clinical setting is the treatment of early stages of DR and, therefore, this review emphasizes in this issue by giving an overview of potential druggable targets. By understanding of disease-specific pathogenic mechanisms, biological heterogeneity and progression patterns in early and advanced DR a more personalised approach to patient treatment will be implemented.


The Perfect Glass Paradigm: Disordered Hyperuniform Glasses Down to Absolute Zero.
Rapid cooling of liquids below a certain temperature range can result in a transition to glassy states. The traditional understanding of glasses includes their thermodynamic metastability with respect to crystals. However, here we present specific examples of interactions that eliminate the possibilities of crystalline and quasicrystalline phases, while creating mechanically stable amorphous glasses down to absolute zero temperature. We show that this can be accomplished by introducing a new ideal state of matter called a "perfect glass". A perfect glass represents a soft-interaction analog of the maximally random jammed (MRJ) packings of hard particles. These latter states can be regarded as the epitome of a glass since they are out of equilibrium, maximally disordered, hyperuniform, mechanically rigid with infinite bulk and shear moduli, and can never crystallize due to configuration-space trapping. Our model perfect glass utilizes two-, three-, and four-body soft interactions while simultaneously retaining the salient attributes of the MRJ state. These models constitute a theoretical proof of concept for perfect glasses and broaden our fundamental understanding of glass physics. A novel feature of equilibrium systems of identical particles interacting with the perfect-glass potential at positive temperature is that they have a non-relativistic speed of sound that is infinite.


Evolution of critical day length for diapause induction enables range expansion of Diorhabda carinulata, a biological control agent against tamarisk (Tamarix spp.).
In classical weed biological control, small collections of arthropods are made from one or a few sites in the native range of the target plant and are introduced to suppress the plant where it has become invasive, often across a wide geographic range. Ecological mismatches in the new range are likely, and success using the biocontrol agent may depend on postrelease evolution of beneficial life history traits. In this study, we measure the evolution of critical day length for diapause induction (day length at which 50% of the population enters dormancy), in a beetle (Diorhabda carinulata) introduced into North America from China to control an exotic shrub, Tamarix spp. Beetle populations were sampled from four sites in North America 7 years after introduction, and critical day length was shown to have declined, forming a cline over a latitudinal gradient At one field site, decreased critical day length was correlated with 16 additional days of reproductive activity, resulting in a closer match between beetle life history and the phenology of Tamarix. These findings indicate an enhanced efficacy and an increasingly wider range for D. carinulata in Tamarix control.


Real-time fMRI pattern decoding and neurofeedback using FRIEND: an FSL-integrated BCI toolbox.
The demonstration that humans can learn to modulate their own brain activity based on feedback of neurophysiological signals opened up exciting opportunities for fundamental and applied neuroscience. Although EEG-based neurofeedback has been long employed both in experimental and clinical investigation, functional MRI (fMRI)-based neurofeedback emerged as a promising method, given its superior spatial resolution and ability to gauge deep cortical and subcortical brain regions. In combination with improved computational approaches, such as pattern recognition analysis (e.g., Support Vector Machines, SVM), fMRI neurofeedback and brain decoding represent key innovations in the field of neuromodulation and functional plasticity. Expansion in this field and its applications critically depend on the existence of freely available, integrated and user-friendly tools for the neuroimaging research community. Here, we introduce FRIEND, a graphic-oriented user-friendly interface package for fMRI neurofeedback and real-time multivoxel pattern decoding. The package integrates routines for image preprocessing in real-time, ROI-based feedback (single-ROI BOLD level and functional connectivity) and brain decoding-based feedback using SVM. FRIEND delivers an intuitive graphic interface with flexible processing pipelines involving optimized procedures embedding widely validated packages, such as FSL and libSVM. In addition, a user-defined visual neurofeedback module allows users to easily design and run fMRI neurofeedback experiments using ROI-based or multivariate classification approaches. FRIEND is open-source and free for non-commercial use. Processing tutorials and extensive documentation are available.


Synergy between quantitative microbial source tracking (qMST) and quantitative microbial risk assessment (QMRA): A review and prospectus.
The use of microbial source tracking (MST) marker genes has grown in recent years due to the need to attribute point and non-point fecal contamination to specific sources. Quantitative microbial risk assessment (QMRA) is a modeling approach used to estimate health risks from exposure to feces-contaminated water and associated pathogens. A combination of these approaches [quantitative MST (qMST) and QMRA] can provide additional pathogen-related information for prioritizing and addressing health risks, compared to reliance on conventional fecal indicator bacteria (FIB). To inform expansion of this approach, a review of published qMST-QMRA studies was conducted to summarize the state of the science and to identify research needs. The reviewed studies primarily aimed to identify what levels of MST marker genes in hypothetical recreational waterbodies would exceed the United States Environmental Protection Agency (USEPA) risk benchmarks for primary contact recreators. The QMRA models calculated relationships between MST marker gene(s) and reference pathogens based on published data in the literature. The development of a robust, accurate relationship was identified as an urgent research gap for qMST-QMRA. This metric requires additional knowledge to quantify the relationship between MST marker genes and the degree of variability in decay of pathogens as a dynamic function of environmental conditions and combinations of fecal sources at multiple spatial and temporal scales. Improved characterization of host shedding rates of host-associated microorganisms (i.e., MST marker genes), as well as fate and transport of these microorganisms and their nucleic acids, would facilitate expansion of this approach to other exposure pathways. Incorporation of information regarding the recovery efficiency, and host-specificity of MST marker genes into QMRA model parameters, and the sensitivity analysis, would greatly improve risk management and site-specific water monitoring criteria.


Dysphagia in Children with Esophageal Atresia: Current Diagnostic Options.
Dysphagia or swallowing disorder is very common (range, 15-52%) in patients with esophageal atresia. Children present with a wide range of symptoms. The most common diagnostic tools to evaluate esophageal dysphagia, such as upper barium study and manometry, aim to characterize anatomy and function of the esophageal body and the esophagogastric junction (EGJ). Using these technologies, a variety of pathological motor patterns have been identified in children with esophageal atresia. However, the most challenging part of diagnosing patients with esophageal dysphagia lies in the fact that these methods fail to link functional symptoms such as dysphagia with the esophageal motor disorders observed. A recent method, called pressure-flow analysis (PFA), uses simultaneously acquired impedance and manometry measurements, and applies an integrated analysis of these recordings to derive quantitative pressure-flow metrics. These pressure-flow metrics allow detection of the interplay between bolus flow, motor patterns, and symptomatology by combining data on bolus transit and bolus flow resistance. Based on a dichotomous categorization, flow resistance at the EGJ and ineffective esophageal bolus transit can be determined. This method has the potential to guide therapeutic decisions for esophageal dysmotility in pediatric patients with esophageal atresia.


Metabolic effects of fasting on human and mouse blood in vivo.
Starvation is a strong physiological stimulus of macroautophagy/autophagy. In this study, we addressed the question as to whether it would be possible to measure autophagy in blood cells after nutrient deprivation. Fasting of mice for 48 h (which causes ∼20% weight loss) or starvation of human volunteers for up to 4 d (which causes <2% weight loss) provokes major changes in the plasma metabolome, yet induces only relatively minor alterations in the intracellular metabolome of circulating leukocytes. White blood cells from mice and human volunteers responded to fasting with a marked reduction in protein lysine acetylation, affecting both nuclear and cytoplasmic compartments. In circulating leukocytes from mice that underwent 48-h fasting, an increase in LC3B lipidation (as assessed by immunoblotting and immunofluorescence) only became detectable if the protease inhibitor leupeptin was injected 2 h before drawing blood. Consistently, measurement of an enhanced autophagic flux was only possible if white blood cells from starved human volunteers were cultured in the presence or absence of leupeptin. Whereas all murine leukocyte subpopulations significantly increased the number of LC3B+ puncta per cell in response to nutrient deprivation, only neutrophils from starved volunteers showed signs of activated autophagy (as determined by a combination of multi-color immunofluorescence, cytofluorometry and image analysis). Altogether, these results suggest that white blood cells are suitable for monitoring autophagic flux. In addition, we propose that the evaluation of protein acetylation in circulating leukocytes can be adopted as a biochemical marker of organismal energetic status.


The fungal vacuole: composition, function, and biogenesis.
The fungal vacuole is an extremely complex organelle that is involved in a wide variety of functions. The vacuole not only carries out degradative processes, the role most often ascribed to it, but also is the primary storage site for certain small molecules and biosynthetic precursors such as basic amino acids and polyphosphate, plays a role in osmoregulation, and is involved in the precise homeostatic regulation of cytosolic ion and basic amino acid concentration and intracellular pH. These many functions necessitate an intricate interaction between the vacuole and the rest of the cell; the vacuole is part of both the secretory and endocytic pathways and is also directly accessible from the cytosol. Because of the various roles and properties of the vacuole, it has been possible to isolate mutants which are defective in various vacuolar functions including the storage and uptake of metabolites, regulation of pH, sorting and processing of vacuolar proteins, and vacuole biogenesis. These mutants show a remarkable degree of genetic overlap, suggesting that these functions are not individual, discrete properties of the vacuole but, rather, are closely interrelated.


Magnaporthe grisea genes for pathogenicity and virulence identified through a series of backcrosses.
We have identified genes for pathogenicity toward rice (Oryza sativa) and genes for virulence toward specific rice cultivars in the plant pathogenic fungus Magnaporthe grisea. A genetic cross was conducted between the weeping lovegrass (Eragrostis curvula) pathogen 4091-5-8, a highly fertile, hermaphroditic laboratory strain, and the rice pathogen O-135, a poorly fertile, female-sterile field isolate that infects weeping lovegrass as well as rice. A six-generation backcrossing scheme was then undertaken with the rice pathogen as the recurrent parent. One goal of these crosses was to generate rice pathogenic progeny with the high fertility characteristic of strain 4091-5-8, which would permit rigorous genetic analysis of rice pathogens. Therefore, progeny strains to be used as parents for backcross generations were chosen only on the basis of fertility. The ratios of pathogenic to nonpathogenic (and virulent to avirulent) progeny through the backcross generations suggested that the starting parent strains differ in two types of genes that control the ability to infect rice. First, they differ by polygenic factors that determine the extent of lesion development achieved by those progeny that infect rice. These genes do not appear to play a role in infection of weeping lovegrass because both parents and all progeny infect weeping lovegrass. Second, the parents differ by simple Mendelian determinants, "avirulence genes," that govern virulence toward specific rice cultivars in all-or-none fashion. Several crosses confirm the segregation of three unlinked avirulence genes, Avr 1-CO39, Avr 1-M201 and Avr1-YAMO, alleles of which determine avirulence on rice cultivars CO39, M201, and Yashiro-mochi, respectively. Interestingly, avirulence alleles of Avr1-CO39, Avr1-M201 and Avr1-YAMO were inherited from the parent strain 4091-5-8, which is a nonpathogen of rice. Middle repetitive DNA sequences ("MGR sequences"), present in approximately 40-50 copies in the genome of the rice pathogen parent, and in very low copy number in the genome of the nonpathogen of rice, were used as physical markers to monitor restoration of the rice pathogen genetic background during introgression of fertility. The introgression of highest levels of fertility into the most successful rice pathogen progeny was incomplete by the sixth generation, perhaps a consequence of genetic linkage between genes for fertility and genes for rice pathogenicity. One chromosomal DNA segment with MGR sequence homology appeared to be linked to the gene Avr1-CO39. Finally, many of the crosses described in this paper exhibited a characteristic common to many crosses involving M. grisea rice pathogen field isolates.(ABSTRACT TRUNCATED AT 400 WORDS)


Using dynamical barriers to control the transmission of light through slowly varying photonic crystals.
We use semiclassical Hamiltonian optics to investigate the propagation of light rays through two-dimensional photonic crystals when slow spatial modulation of the lattice parameters induces mixed stable-chaotic ray dynamics. This modulation changes both the shape and frequency range of the allowed frequency bands, thereby bending the resulting semiclassical ray trajectories and confining them within particular regions of the crystal. The curved boundaries of these regions, combined with the bending of the orbits themselves, creates a hierarchy of stable and unstable chaotic trajectories in phase space. For certain lattice parameters and electromagnetic wave frequencies, islands of stable orbits act as a dynamical barrier, which separates the chaotic trajectories into two distinct regions of the crystal, thereby preventing the rays propagating through the structure. We show that changing the frequency of the electromagnetic wave strongly affects the distribution of stable and unstable orbits in both real and phase space. This switches the dynamical barriers on and off and thus modulates the transmission of rays through the crystal. We propose microwave analogs of the photonic crystals as a route to the experimental study of the transport effects that we predict.


High resolution computed tomographic findings in pulmonary tuberculosis.
Although chest radiographs usually provide adequate information for the diagnosis of active pulmonary tuberculosis, minimal exudative tuberculosis can be overlooked on standard chest radiographs. The aim of the present study was to assess the findings of active pulmonary tuberculosis on high resolution computed tomographic (HRCT) scans, and to evaluate their possible use in determining disease activity. Thirty two patients with newly diagnosed active pulmonary tuberculosis and 34 patients with inactive pulmonary tuberculosis were examined. The diagnosis of active pulmonary tuberculosis was based on positive acid fast bacilli in sputum and bronchial washing smears or cultures and/or changes on serial radiographs obtained during treatment. With HRCT scanning centrilobular lesions (n = 29), "tree-in-bud" appearance (n = 23), and macronodules 5-8 mm in diameter (n = 22) were most commonly seen in cases of active pulmonary tuberculosis. HRCT scans showed fibrotic lesions (n = 34), distortion of bronchovascular structures (n = 32), emphysema (n = 28), and bronchiectasis (n = 24) in patients with inactive tuberculosis. Centrilobular densities in and around the small airways and "tree-in-bud" appearances were the most characteristic CT features of disease activity. HRCT scanning clearly differentiated old fibrotic lesions from new active lesions and demonstrated early bronchogenic spread. These findings may be of value in decisions on treatment.


Quantity and quality limit detritivore growth: mechanisms revealed by ecological stoichiometry and co-limitation theory.
Resource quantity and quality are fundamental bottom-up constraints on consumers. Best understood in autotroph-based systems, co-occurrence of these constraints may be common but remains poorly studied in detrital-based systems. Here, we used a laboratory growth experiment to test limitation of the detritivorous caddisfly larvae Pycnopsyche lepida across a concurrent gradient of oak litter quantity (food supply) and quality (phosphorus : carbon [P:C ratios]). Growth increased simultaneously with quantity and quality, indicating co-limitation across the resource gradients. We merged approaches of ecological stoichiometry and co-limitation theory, showing how co-limitation reflected shifts in C and P acquisition throughout homeostatic regulation. Increased growth was best explained by elevated consumption rates and improved P assimilation, which both increased with elevated quantity and quality. Notably, C assimilation efficiencies remained unchanged and achieved maximum 18% at low quantity despite pronounced C limitation. Detrital C recalcitrance and substantive post-assimilatory C losses probably set a minimum quantity threshold to achieve positive C balance. Above this threshold, greater quality enhanced larval growth probably by improving P assimilation toward P-intensive growth. We suggest this interplay of C and P acquisition contributes to detritivore co-limitation, highlighting quantity and quality as potential simultaneous bottom-up controls in detrital-based ecosystems, including under anthropogenic change like nutrient enrichment.


Using an efficient biofilm detaching agent: an essential step for the improvement of endoscope reprocessing protocols.
Biofilms develop inside endoscope channels even when valid endoscope reprocessing protocols are applied. The use of an efficient biocide is not sufficient if the channels are not cleaned thoroughly prior to disinfection. This study compared new anti-biofilm combinations of detachment promoting agents with a cleaning product in current use. Tests were performed using Teflon tubing and a contamination device that reproduces conditions that are prevalent during endoscopy. Products were subjected to static+brushing or dynamic treatments, and their ability to remove a preformed biofilm was assessed. The residual biofilm after treatment was assessed and compared with untreated controls. The percentage of surface covered by biofilm was measured after staining with crystal violet. Culturable bacteria levels were determined by plating the bacteria scraped from the tubing surface and counting the colony-forming units (CFU). Further tests were performed on actual endoscopes that had been contaminated artificially. Biofilm removal was confirmed by scanning electron microscopy. This study showed that the new anti-biofilm products prevented the build-up of biofilm and removed a mature biofilm (approximately 10(8)CFU/cm(2)), whereas protocols based on detergent-disinfectants containing quaternary ammonium compounds showed low efficacy as these protocols and products fixed the biofilm on the endoscope surfaces. The new procedure and agents represent a new approach to biofilm control that may improve the efficacy of endoscope reprocessing, and reduce the risk of transmitting infections.


Impact of a Surgeon-Led Peripherally Inserted Central Venous Catheter Team on Peripherally Inserted Central Venous Catheter-Related Complications and Costs.
Peripherally inserted central venous catheters (PICCs) are popular for a broad range of indications. As with other forms of central access, PICC use can be associated with serious and potentially costly complications. In 2000, in response to the rising popularity of PICC use, a surgeon-led team was created to steward their placement. All requests were screened rigorously to ensure rational use. Our hypothesis was that creation of a dedicated PICC team would decrease inappropriate PICC placement, overall complication rates, and cost. The study was a retrospective review of prospectively collected data captured in the PICC team-maintained database between 2000 and 2013. The database was reviewed for PICC indications, reasons PICC requests were denied, and septic or thrombotic complications after PICC placement. To estimate cost savings, PICC supplies and each occurrence of blood stream infection (BSI) and thrombotic complication was assigned a cost on the basis of the available literature. Between 2000 and 2013, 35,651 PICC placements were requested, of which 24,638 (69.1%) were approved, 22,157 (62.1%) immediately and 2,481 (6.9%) after initial refusal in view of further review of the indications. Most (95%) of the PICCs inserted were placed at the bedside within 1 d of approval. Blood stream infections occurred in 5.9% of patients and thrombosis in 2.7%. The attributable costs saved by declining placement of unnecessary PICCs, assuming the same proportions of patients would have developed a complication, could be as high as $5.4 million (M) in supplies, $7.77 M in avoided BSI and $2.25 M in avoided thrombotic complications, for a total savings of $15.44 M. The implementation of a surgeon-led PICC team had a significant impact on the placement rate, reducing cost by supplies foregone and complications avoided. Cost savings related to PICC placement alone should be considered as the definite cost savings because of the judicious allocation of resources.


Improved Recovery Experience Achieved for Women Undergoing Implant-Based Breast Reconstruction Using an Enhanced Recovery after Surgery Model.
Enhanced recovery after surgery was compared with traditional recovery after surgery for postmastectomy alloplastic breast reconstruction. Length of stay, emergency room visits, and complications within 30 days of surgery were compared among three groups: traditional recovery after surgery, transition (some elements of enhanced recovery protocol, not transitioned to outpatient care), and enhanced recovery after surgery (day surgery, provided with standardized perioperative education and multimodal analgesia). Prospective data collection allowed quality-of-recovery assessment using a validated questionnaire for enhanced recovery/transition groups. Results were statistically analyzed (analysis of variance/chi-square). The traditional recovery, transition, and enhanced recovery cohorts comprised 29, 11, and 29 patients, respectively. No significant differences were present regarding age, smoking status, preoperative radiation, single stage direct-to-implant versus tissue expander, bilateral versus unilateral surgery, or immediate versus delayed reconstruction among groups. Average length of stay was 1.6 nights in both the traditional recovery and transition groups, compared with 0 nights in the enhanced recovery group (p < 0.001). Enhanced recovery patients had less severe pain (p = 0.02) and nausea (p = 0.01), and better enjoyed their food (p = 0.0002) and felt more rested (p = 0.02) than their transition counterparts. There were no differences in the number of emergency room visits among the three groups (p = 0.88). There was no difference in the rate of hematoma (p = 0.36), infection requiring intravenous antibiotics (p = 0.36), or infection requiring explantation (p = 0.36) among the three groups. An enhanced recovery protocol for alloplastic breast reconstruction treated patients safely, with improved patient satisfaction and same-day discharge and with no increase in complications. Therapeutic, III.


Negative childhood experiences alter a prefrontal-insular-motor cortical network in healthy adults: A preliminary multimodal rsfMRI-fMRI-MRS-dMRI study.
Research in humans and animals has shown that negative childhood experiences (NCE) can have long-term effects on the structure and function of the brain. Alterations have been noted in grey and white matter, in the brain's resting state, on the glutamatergic system, and on neural and behavioural responses to aversive stimuli. These effects can be linked to psychiatric disorder such as depression and anxiety disorders that are influenced by excessive exposure to early life stressors. The aim of the current study was to investigate the effect of NCEs on these systems. Resting state functional MRI (rsfMRI), aversion task fMRI, glutamate magnetic resonance spectroscopy (MRS), and diffusion magnetic resonance imaging (dMRI) were combined with the Childhood Trauma Questionnaire (CTQ) in healthy subjects to examine the impact of NCEs on the brain. Low CTQ scores, a measure of NCEs, were related to higher resting state glutamate levels and higher resting state entropy in the medial prefrontal cortex (mPFC). CTQ scores, mPFC glutamate and entropy, correlated with neural BOLD responses to the anticipation of aversive stimuli in regions throughout the aversion-related network, with strong correlations between all measures in the motor cortex and left insula. Structural connectivity strength, measured using mean fractional anisotropy, between the mPFC and left insula correlated to aversion-related signal changes in the motor cortex. These findings highlight the impact of NCEs on multiple inter-related brain systems. In particular, they highlight the role of a prefrontal-insular-motor cortical network in the processing and responsivity to aversive stimuli and its potential adaptability by NCEs.


Household Migration, Remittances, and Its Impact on Health in Indonesia.
The growing flow of migrant's remittances has generated much interest in understanding the socioeconomic consequences of household migration for individuals and families in migrant-sending areas. This paper examines the effect of household migration on health status, as measured by nutritional status, of adults who remained behind in rural Indonesia, a setting with high rate of out-migration and poor nutritional profiles. Assuming that remittances may improve household economic resources and thus change dietary intake and health-related investment, household migration may be associated with both the risks of undernutrition and overnutrition. The analyses use longitudinal data from the Indonesian Family Life Survey and fixed-effect regressions. The results show that adults in emigrant household were significantly less susceptible to being underweight than those in non-migrant households, but they did not have increased risk of being overweight. The improved nutritional status was restricted to people in households with labor migrants, highlighting the role of remittances in improving nutritional intake. The health gain also was concentrated among women, increased with the number of out-migrants, and was revealed over time as remittances arrived. Overall, this study demonstrates the beneficial role of household migration, especially the resulting remittances, in the health status of household members in resource-constrained settings. Improving transfers of remittances would be helpful in reducing the problem of undernutrition in poor migrant-sending areas.


Studies on the pharmacokinetics and metabolism of 4-chlorodiphenyl ether in rats.
The metabolic disposition of 14C-labeled 4-chlorodiphenyl ether ([14C]4-CDE) was examined in rats following iv administration of a single dose (850 nmol/kg). [14C]4-CDE decayed rapidly from the blood since no unchanged [14C]4-CDE was detected in the blood beyond 2 hr after [14C]4-CDE administration. The dispositional kinetics of [14C]4-CDE in rats were best described by a two-compartment open pharmacokinetic model. Total radioactivity was excreted slowly from rats; about 41% and 33% of the administered dose were excreted into the urine and feces, respectively, within 1 week after chemical administration. About 5% of the total radioactivity administered to rats was excreted into the bile in 1 hr. The bulk of the radioactivity in the excreta was due to the presence of [14C]4-CDE metabolites. 14C-labeled 4'-hydroxy-4-CDE was the major metabolite and accounted for at least 90% of the radioactivity in the urine. The metabolic conversion of [14C]4-CDE to 14C-labeled 4'-hydroxy-4-CDE was corroborated by in vitro studies with liver microsomes of rats. In addition, [14C]4-CDE was converted by liver microsomes to reactive metabolites which bound irreversibly to microsomal protein. An arene oxide is suggested as the intermediate metabolite in the biotransformation of [14C]4-CDE by rats.


Detection of chromium in wastewater from refuse incineration power plant near Poyang Lake by laser induced breakdown spectroscopy.
A laser induced breakdown spectroscopy (LIBS) system was developed for determination of toxic metals Cr in wastewater collected from a refuse incineration power plant near Poyang Lake. The plasma was generated by focusing a pulsed Nd:YAG laser at 1064 nm on the surface of liquid. Experimental conditions were optimized for improving the sensitivity and repeatability of the LIBS system through a parametric dependence study in potassium bichromate (K(2)Cr(2)O(7)) aqueous solutions. Calibration curves for Cr I 425.43 and 357.87 nm lines are compared and the limit of detection is found to be 39 and 86 ppm, respectively. This calibration curve of Cr I 425.43 nm has been used for quantification of Cr in wastewater collected from a refuse incineration power plant near Poyang Lake where the concentration of Cr is found to be 97 ppm. The results between LIBS and standard analytical technique such as atomic absorption spectroscopy were compared, and the relative standard deviation was 8.5%.


Prospective association of adiposity and cardiorespiratory fitness with cardiovascular risk factors in healthy children.
This study aimed to examine the prospective association of three different measures of adiposity and cardiorespiratory fitness (CRF) with 2-year change in cardiovascular disease (CVD) risk factors in children. Two-year longitudinal data in schoolchildren aged 7-11 years (n = 365-729) was used. Total body fat (TBF) from dual-energy x-ray absorptiometry, body mass index (BMI), waist circumference (WC), CRF, blood samples, and blood pressure were obtained in 2008 and 2010 in the Childhood Health, Activity, and Motor Performance School Study in Denmark (CHAMPS study-DK). Greater adiposity at baseline was associated with increased CVD risk factor levels at follow-up. The magnitudes of associations were similar regardless of adiposity measure [TBF%: β 0.30, 95% confidence interval (CI): 0.21-0.39; BMI: β 0.24, 95% CI: 0.14-0.33; WC: β 0.20, 95% CI: 0.10-0.31], and no evidence of nonlinear relationships was observed. We found less strong associations of CRF with increase in CVD risk factor levels after adjusting for adiposity; however, increasing CRF was still favorably associated with decrease in CVD risk factor levels among boys. Results suggest that any effort to shift the population distribution of adiposity downward would be valuable for early CVD prevention. The association of CRF with CVD risk factors was largely explained by adiposity, particularly among girls.


Tyrosine-free amino acid mixtures reduce physiologically-evoked release of dopamine in a selective and activity-dependent manner.
Depletion of the catecholamine precursor tyrosine using tyrosine-free amino acid mixtures is an important tool in neuropsychological studies, and often considered dopamine selective on the basis of neuropharmacological studies. However, little is known of the effects of tyrosine depletion when catecholamine neurons are activated physiologically. Here we investigated the effect of tyrosine-free amino acid mixtures on catecholamine release evoked in vivo using a stimulation paradigm aimed to approximate the phasic firing pattern of these neurons that accompanies cognitive and behavioural change. Dopamine and noradrenaline release was monitored by microdialysis in rat medial prefrontal cortex (mPFC) and striatum (chloral hydrate anaesthesia, perfusion medium containing 1 µM cocaine). Electrical stimulation of the medial forebrain bundle (MFB) caused a short-lasting, frequency-dependent increase in dopamine and noradrenaline. A full tyrosine-free amino acid mixture reduced the release of dopamine in mPFC and striatum, across a range of stimulation frequencies, and the effect was greater as stimulation frequency increased. Similar results were obtained using a smaller tyrosine-free amino acid mixture. In the same experiments showing decreased dopamine, neither tyrosine-free mixture of amino acids significantly altered stimulation-evoked release of noradrenaline. These results show that tyrosine depletion using tyrosine-free amino acid mixtures causes a selective, activity-dependent decrease in dopamine release when dopamine neurons are driven physiologically.


Mapping and characterization of visna/maedi virus cytotoxic T-lymphocyte epitopes.
CD8(+) cytotoxic T-lymphocyte (CTL) responses have been shown to be important in the control of human and simian immunodeficiency virus infections. Infection of sheep with visna/maedi virus (VISNA), a related lentivirus, induces specific CD8(+) CTL in vivo, but the specific viral proteins recognized are not known. To determine which VISNA antigens were recognized by sheep CTL, we used recombinant vaccinia viruses expressing the different genes of VISNA: in six sheep (Finnish LandracexDorset crosses, Friesland and Lleyn breeds) all VISNA proteins were recognized except TAT. Two sheep, shown to share major histocompatibility complex (MHC) class I alleles, recognized POL and were used to map the epitope. The pol gene is 3267 bp long encoding 1088 aa. By using recombinant vaccinia viruses a central portion (nt 1609-2176, aa 537-725) was found to contain the CTL epitope and this was mapped with synthetic peptides to a 25 aa region (aa 612-636). When smaller peptides were used, a cluster of epitopes was detected: at least three epitopes were present, at positions 612-623: DSRYAFEFMIRN; 620-631: MIRNWDEEVIKN; and 625-635: EEVIKNPIQAR. A DNA-prime-modified vaccinia virus Ankara (MVA)-boost strategy was employed to immunize four sheep shown to share MHC class I allele(s) with the sheep above. Specific CTL activity developed in all the immunized sheep within 3 weeks of the final MVA boost although half the sheep showed evidence of specific reactivity after the DNA-prime immunizations. This is the first report, to our knowledge, of induction of CTL by a DNA-prime-boost method in VISNA infection.


Diabetes mellitus and hypothyroidism: Strange bedfellows or mutual companions?
Clinicians should be cognizant of the close relationship that exists between two of the most common endocrine disorders, primary hypothyroidism and diabetes mellitus. This applies to patients with both type 1 and type 2 diabetes mellitus (T1DM and T2DM respectively). However, the association is greater in T1DM, probably because of the shared autoimmune predisposition. In patients with T2DM, the relationship is somewhat weaker and the explanation less clear-cut. Factors such as dietary iodine deficiency, metformin-induced thyroid stimulating hormone suppression and poor glycemic control may all be implicated. Further translational research is required for greater clarification. Biochemical screening for abnormal thyroid function in individuals who have diabetes is warranted, particularly in females with T1DM, and therapy with L-thyroxine appropriately instituted if hypothyroidism is confirmed.


Uncoupling protein 2 polymorphisms as risk factors for NTDs.
Both environmental and genetic factors are involved in the etiology of NTDs. Inadequate folate intake and obesity are important environmental risk factors. Several folate-related genetic variants have been identified as risk factors; however, little is known about how genetic variants relate to the increased risk seen in obese women. Uncoupling Protein 2 (UCP2) is an attractive candidate to screen for NTD risk because of its possible role in obesity as well as energy metabolism, type-2 diabetes, and the regulation of reactive oxygen species. Interestingly, a previous study found that a common UCP2 compound homozygous genotype was associated with a threefold increase in NTD risk. We evaluated three polymorphisms, -866G>A, A55V, and the 3'UTR 45 bp insertion/deletion, as risk factors for NTDs in Irish NTD cases (n = 169), their mothers (n = 163), their fathers (n = 167), and normal control subjects (n = 332). Allele and genotype frequencies were not significantly different when comparing NTD mothers, NTD fathers, or affected children to controls. Additionally, the previously reported risk genotype (combined homozygosity of 55VV and 3'UTR 45 bp deletion/deletion) was not present at a higher frequency in any NTD group when compared to controls. In our Irish study population, UCP2 polymorphisms did not influence NTD risk. Moreover, the prevalence of this allele in other populations was similar to the Irish prevalence but far lower than reported in the previous NTD study, suggesting that this previous finding of an association with NTDs might have been due to an unrepresentative study sample.


Methicillin-resistant S. aureus (MRSA), extended-spectrum (ESBL)- and plasmid-mediated AmpC ß-lactamase -producing Gram-negative bacteria associated with skin and soft tissue infections in hospital and community settings.
To investigate the characteristics of meticillin-resistant S. aureus (MRSA), extended-spectrum (ESBL), and plasmid-mediated AmpC beta-lactamase producing Gram-negative bacteria causing skin and soft tissue infections (SSTIs) in hospital and outpatient settings of Zenica-Doboj Canton, Bosnia and Herzegovina. Antibiotic susceptibility was determined by disc-diffusion and broth microdillution methods according to CLSI guidelines. MecA gene was detected by PCR, and genetic characterization of MRSA was performed using spa-typing and the algorithm based upon repeat patterns (BURP). Double-disk-synergy test was used to screen for ESBLs. PCR was used to detect blaESBL alleles. Genetic relatedness of the strains was tested by PFGE. Seventeen in-patients with MRSA, 13 with ESBL-producing Gram-negative bacteria and three patients co-infected with both, were detected. Five MRSA and 16 ESBL-producing Gram-negative bacteria were found in outpatient samples. Klebsiella spp. was isolated in 11 in- and seven outpatients. MLST CC152 was the most prevalent MRSA. Seven (38.9%) Klebsiella spp. yielded amplicons with primers specific for SHV, TEM-1 and CTX-M group 1 β-lactamases. Eight K. pneumonia (44.4%) and 16 (64%) MRSA (including the in- and outpatient) strains were clonally related. The presence of MRSA and ESBL-producing organisms causing SSTIs in the community poses a substantial concern, due to the high morbidity and mortality associated with possible consequent hospital infections.


On the Large Near-Field Enhancement on Nanocolumnar Gold Substrates.
One of the most important and distinctive features of plasmonic nanostructures is their ability to confine large electromagnetic fields on nanometric volumes; i.e., the so-called hot spots. The generation, control and characterization of the hot spots are fundamental for several applications, like surface-enhanced spectroscopies. In this work, we characterize the near-field distribution and enhancement of nanostructured gold thin films fabricated by glancing angle deposition magnetron sputtering. These films are composed of columnar nanostructures with high roughness and high density of inter-columnar gaps, where the electromagnetic radiation can be confined, generating hot spots. As expected, the hot spots are localized in the gaps between adjacent nanocolumns and we use scattering-type scanning near-field optical microscopy to image their distribution over the surface of the samples. The experimental results are compared with finite-difference time-domain simulations, finding an excellent agreement between them. The spectral dependence of the field-enhancement is also studied with the simulations, together with surface-enhanced Raman spectroscopy at different excitation wavelengths in the visible-NIR range, proving a broad-band response of the substrates. These findings may result in interesting applications in the field of surface-enhanced optical spectroscopies or sensing.


A multicenter case control study of association of vitamin D with breast cancer among women in Karachi, Pakistan.
The prevalence of vitamin D inadequacy and breast cancer are both high among women living in Karachi, Pakistan. A matched case control study was conducted in two hospitals of Karachi, Pakistan to evaluate the association of vitamin D (serum 25-hydroxyvitamin D) concentrations, vitamin D supplementation and sun exposure with breast cancer among Pakistani women. A total of 411 newly diagnosed histologically confirmed primary breast cancer cases were enrolled and 784 controls, free of breast and any other cancers, were matched by age (year of birth ± 5 years), residence in the same geographic area and study site. Information was collected on sociodemographic history, history of vitamin D supplementation, past medical and obstetrical history, family history of breast cancer, sun exposure history, histopathology reports and anthropometric measurement and venous blood was collected to measure serum 25-hydroxyvitamin D (25(OH)D) concentration. Compared to patients with sufficient serum vitamin D (>30 ng/ml), women with serum vitamin D deficiency (<20ng/ml), had a higher risk of breast cancer (OR = 1.65, 95%CI: 1.10, 2.50). Women with history of vitamin D supplementation one year prior to enrollment, had significant protective effect against breast cancer (OR = 0.32, 95% CI: 0.24, 0.43). Serum vitamin D deficiency was associated with increased risk of breast cancer, while vitamin D supplementation was associated with decreased risk of breast cancer. In Pakistani women, where vitamin D deficiency is common, raising and maintaining serum vitamin D at population level is a safe and affordable strategy. It may play a role in reducing the incidence of both vitamin D deficiency and breast cancer, particularly among poor women where the breast cancer mortality is highest due to limited resources for early detection, diagnosis, and treatment. The effects of vitamin D with regard to breast cancer risk in Karachi Pakistan should be further evaluated.


OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY OF THE FOVEA IN CHILDREN BORN PRETERM.
To compare the foveal avascular zone (FAZ) area measured by optical coherence tomography angiography in children who had been born preterm with age-matched controls. In this cross-sectional observational comparative case series, 43 eyes of 26 children (28 eyes of 15 former preterm infants and 15 eyes of 11 former term infants) between the ages of 4 and 12 years old were included. Optical coherence tomography angiography with a scan size of 3 × 3 was performed for all eyes. Foveal avascular zone area was measured using the Optovue RTVue AVANTI instrument (Optovue Inc, Fremont, CA) software. Inner and outer retinal thicknesses were measured with the instrument caliper. A distinct FAZ was absent in 12 eyes (42.8%) of children with a history of preterm birth, however, it was present in all (100%) control eyes. The FAZ area was significantly correlated with gestational age (r = 0.82, P < 0.001) and birth weight (r = 0.80, P < 0.001). The gestational age was less than 29 weeks and birth weight was less than 1,480 grams in eyes with no distinct FAZ. Mean central foveal vessel density in the superficial capillary plexus was 41.8 ± 4.4% in the preterm group and 32.8 ± 5.8% in the control group (P < 0.001). In all eyes, a significant negative correlation was found between the central foveal vessel density and gestational age (r = -0.63, P = 0.001) and birth weight (r = -0.59, P = 0.002). On spectral domain optical coherence tomography examination, the foveal depression was absent and the inner retinal layers were preserved in all eyes with absent FAZ. In all eyes, a significant negative correlation was found between the inner retinal thickness and gestational age (r = -0.68, P < 0.001) and birth weight (r = -0.61, P = 0.001). Ten eyes of 6 preterm children had a history of laser therapy for retinopathy of prematurity. A distinct FAZ was absent in six eyes (60%) with retinopathy of prematurity with history of laser therapy, and six eyes (33.3%) with preterm birth without laser therapy. Eyes with history of laser therapy had a statistically significantly higher inner retinal thickness and central foveal vessel density and smaller FAZ compared with the eyes with preterm birth without laser therapy (P < 0.001, P = 0.04 and P = 0.03, respectively). Optical coherence tomography angiography is a novel modality for noninvasive visualization of the retinal vasculature in pediatric patients and expands our knowledge of foveal abnormalities in retinopathy of prematurity. A small or absent FAZ seems to be a distinct sign of prematurity.


Simulating fields of arbitrary spatial and temporal coherence.
Optical coherence theory typically deals with the average properties of randomly fluctuating fields. However, in some circumstances the averaging process can mask important physical aspects of the field propagation. We derive a new method of simulating partially coherent fields of nearly arbitrary spatial and temporal coherence. These simulations produce the expected coherence properties when averaged over sufficently long time intervals. Examples of numerous fields are given, and an analytic formula for the intensity fluctuations of the field is given. The method is applied to the propagation of partially coherent fields through random phase screens.


Extended culture and imaging of normal and regenerating adult zebrafish hearts in a fluidic device.
Myocardial infarction and heart failure are leading causes of death worldwide, in large part because adult human myocardium has extremely limited regeneration capacity. Zebrafish are a powerful model for identifying new strategies for human cardiac repair because their hearts regenerate after relatively severe injuries. Zebrafish are also relatively scalable and compatible with many genetic tools. However, characterizing the regeneration process in live adult zebrafish hearts has proved challenging because adult fish are opaque, preventing live imaging in vivo. An alternative strategy is to explant and culture intact adult zebrafish hearts and investigate them ex vivo. However, explanted hearts maintained in conventional culture conditions experience rapid declines in morphology and physiology. To overcome these limitations, we designed and fabricated a fluidic device for culturing explanted adult zebrafish hearts with constant media perfusion that is also compatible with live imaging. We then compared the morphology and calcium activity of hearts cultured in the device, hearts cultured statically in dishes, and freshly explanted hearts. After one week of culture, hearts in the device experienced significantly less morphological degradation compared to hearts cultured in dishes. Hearts cultured in devices for one week also maintained capture rates similar to fresh hearts, unlike hearts cultured in dishes. We then cultured explanted injured hearts in the device and used live imaging techniques to continuously record the myocardial revascularization process over several days, demonstrating how our device is compatible with long-term live imaging and thereby enables unprecedented visual access to the multi-day process of adult zebrafish heart regeneration.


Cervical Versus Thoracolumbar Spinal Deformities: A Comparison of Baseline Quality-of-Life Burden.
Retrospective analysis of 2 prospectively collected multicenter databases, one for cervical deformity (CD) and the other for general adult spinal deformity. To investigate the relative quality-of-life and disability burden in patients with uncompensated cervical, thoracolumbar, or cervical and thoracolumbar deformities. The relative quality-of-life burden of cervical and thoracolumbar deformities have never been compared with each other. This may have significant implications when deciding on the appropriate treatment intervention for patients with combined thoracolumbar and cervical deformities. When defining CD C2-C7 sagittal vertical axis (SVA)>4 cm was used while a C7-S1 SVA>5 cm was used to defined thoracolumbar deformity. Patients with both SVA criteria were defined as "combined." Primary analysis compared patients in the different groups by demographic, comorbidity data, and quality-of-life scores [EuroQOL 5 dimensions questionnaire (EQ-5D)] using t tests. Secondary analysis matched deformity groups with propensity scores matching based on baseline EQ-5D scores. Differences in disease-specific metrics [the Oswestry Disability Index, Neck Disability Index, modified Japanese Orthopaedic Association questionnaire (mJOA)] were analyzed using analysis of variance tests and post hoc analysis. In total, 212 patients were included in our analysis. Patients with CD only had less neurological deficits (mJOA: 14.6) and better EQ-5D (0.746) scores compared with patients with combined deformities (11.9, 0.716), all P<0.05. Regarding propensity score-matched deformity cohorts, 99 patients were matched with similar quality-of-life burden, 33 per deformity cohort. CD only patients had fewer comorbidities (1.03 vs. 2.12 vs. 2.70; P<0.001), whereas patients with combined deformity had more baseline neurological impairment compared with CD only patients (mJOA: 12.00 vs. 14.25; P=0.050). Combined deformity patients were associated with the lowest quality-of-life and highest disability. Furthermore, regarding deformity cohorts matched by similar baseline quality-of-life status (EQ-5D), patients with combined deformities were associated with significantly worse neurological impairments. This finding implies that quality of life may not be a direct reflection of a patient's disability status, especially in patients with combined cervical and thoracolumbar deformities. Level III.


MaLT - Combined Motor and Language Therapy Tool for Brain Injury Patients Using Kinect.
The functional connectivity and structural proximity of elements of the language and motor systems result in frequent co-morbidity post brain injury. Although rehabilitation services are becoming increasingly multidisciplinary and "integrated", treatment for language and motor functions often occurs in isolation. Thus, behavioural therapies which promote neural reorganisation do not reflect the high intersystem connectivity of the neurologically intact brain. As such, there is a pressing need for rehabilitation tools which better reflect and target the impaired cognitive networks. The objective of this research is to develop a combined high dosage therapy tool for language and motor rehabilitation. The rehabilitation therapy tool developed, MaLT (Motor and Language Therapy), comprises a suite of computer games targeting both language and motor therapy that use the Kinect sensor as an interaction device. The games developed are intended for use in the home environment over prolonged periods of time. In order to track patients' engagement with the games and their rehabilitation progress, the game records patient performance data for the therapist to interrogate. MaLT incorporates Kinect-based games, a database of objects and language parameters, and a reporting tool for therapists. Games have been developed that target four major language therapy tasks involving single word comprehension, initial phoneme identification, rhyme identification and a naming task. These tasks have 8 levels each increasing in difficulty. A database of 750 objects is used to programmatically generate appropriate questions for the game, providing both targeted therapy and unique gameplay every time. The design of the games has been informed by therapists and by discussions with a Public Patient Involvement (PPI) group. Pilot MaLT trials have been conducted with three stroke survivors for the duration of 6 to 8 weeks. Patients' performance is monitored through MaLT's reporting facility presented as graphs plotted from patient game data. Performance indicators include reaction time, accuracy, number of incorrect responses and hand use. The resultant games have also been tested by the PPI with a positive response and further suggestions for future modifications made. MaLT provides a tool that innovatively combines motor and language therapy for high dosage rehabilitation in the home. It has demonstrated that motion sensor technology can be successfully combined with a language therapy task to target both upper limb and linguistic impairment in patients following brain injury. The initial studies on stroke survivors have demonstrated that the combined therapy approach is viable and the outputs of this study will inform planned larger scale future trials.


Healing of spongiosus-cutaneous fistula with hyperbaric Oxygen Therapy (HBOT): a case report.
We present a case of a spongiosus-cutaneous fistula in a 39-year-old man with recurrent episodes of cutaneous abscess in dorsal middle third penis (5 × 3 cm) treated with Hyperbaric Oxygen Therapy (HBOT). After emptying nodular abscess, the patient was noncompliant for further surgery. Therefore, it was suggested the association between HBOT and antibiotic therapy. HBOT is carried out in a hyperbaric room, where the internal pressure is increased (compression phase) by entering compressed air up to 283.71 kPa in about 10 minutes. Every HBOT cycle lasted 24 days in which the patient had been taking Amoxicillin/Clavulanic Acid 875 mg/125 mg 3 tabs/day and Sulfamethoxazole/Trimethoprim 160 mg/800 mg 2 tabs/day for 2 weeks. At the end of the treatment, a penile magnetic resonance imaging and an ultrasonography were executed and they evidenced a complete remission of the lesion. In the subsequent 22 months, there was no recurrence. Our results suggest that HBOT is an effective treatment for chronic wounds, including a spongiosus-cutaneous fistula of unknown cause, when used in combination with conventional standard therapy or further interventions. At present time, the gold standard remains surgery; nevertheless, our experience with HBOT may stimulate its use in clinical trials.


Maternal Folic Acid Supplementation During Pregnancy and Early Childhood Asthma.
Asthma is one of the most common chronic childhood diseases. While folic acid supplementation around conception helps prevent neural tube defects, an animal model suggests that it may be a risk factor for respiratory diseases, although epidemiologic studies have had conflicting results. We investigated the timing of folic acid-containing prescription filling during pregnancy and child asthma. In a retrospective cohort study of 104,428 children, born 1996-2005, and their mothers enrolled in Tennessee Medicaid, we investigated the association of filling folic acid-containing prescriptions during pregnancy and childhood asthma at ages 4.5-6 years. We categorized women into exposure groups based on prescription filling centered around the first trimester: no folic acid prescription exposure, exposure in first trimester only, exposure after first trimester, and exposure in first trimester and beyond. We defined asthma using asthma-specific healthcare visits and medication fills. Using logistic regression models, we investigated the relationship adjusting for potential confounders. Overall 15% of children had asthma. Compared with children born to women with no folic acid prescription exposure, children born to women with exposures in the first trimester only or first trimester and later had increased relative odds of asthma (adjusted odds ratios = 1.2, 95% confidence interval = 1.1, 1.3, and 1.2, 95% confidence interval = 1.2, 1.3); no association was seen in children born to women exposed after the first trimester. Timing of folic acid-containing prescription filling during pregnancy was associated with childhood asthma. Our findings contribute to understanding of the role of prenatal nutritional supplements on child respiratory health.


The effect of multiple primary rules on population-based cancer survival.
Different rules for registering multiple primary (MP) cancers are used by cancer registries throughout the world, making international data comparisons difficult. This study evaluates the effect of Surveillance, Epidemiology, and End Results (SEER) and International Association of Cancer Registries (IACR) MP rules on population-based cancer survival estimates. Data from five US states and six metropolitan area cancer registries participating in the SEER Program were used to estimate age-standardized relative survival (RS%) for first cancers-only and all first cancers matching the selection criteria according to SEER and IACR MP rules for all cancer sites combined and for the top 25 cancer site groups among men and women. During 1995-2008, the percentage of MP cancers (all sites, both sexes) increased 25.4 % by using SEER rules (from 14.6 to 18.4 %) and 20.1 % by using IACR rules (from 13.2 to 15.8 %). More MP cancers were registered among females than among males, and SEER rules registered more MP cancers than IACR rules (15.8 vs. 14.4 % among males; 17.2 vs. 14.5 % among females). The top 3 cancer sites with the largest differences were melanoma (5.8 %), urinary bladder (3.5 %), and kidney and renal pelvis (2.9 %) among males, and breast (5.9 %), melanoma (3.9 %), and urinary bladder (3.4 %) among females. Five-year survival estimates (all sites combined) restricted to first primary cancers-only were higher than estimates by using first site-specific primaries (SEER or IACR rules), and for 11 of 21 sites among males and 11 of 23 sites among females. SEER estimates are comparable to IACR estimates for all site-specific cancers and marginally higher for all sites combined among females (RS 62.28 vs. 61.96 %). Survival after diagnosis has improved for many leading cancers. However, cancer patients remain at risk of subsequent cancers. Survival estimates based on first cancers-only exclude a large and increasing number of MP cancers. To produce clinically and epidemiologically relevant and less biased cancer survival estimates, data on all cancers should be included in the analysis. The multiple primary rules (SEER or IACR) used to identify primary cancers do not affect survival estimates if all first cancers matching the selection criteria are used to produce site-specific survival estimates.


Mineralocorticoid action: target tissue specificity is enzyme, not receptor, mediated.
Mineralocorticoid receptors, both when in tissue extracts and when recombinant-derived, have equal affinity for the physiological mineralocorticoid aldosterone and for the glucocorticoids cortisol and corticosterone, which circulate at much higher concentrations than aldosterone. Such receptors are found in physiological mineralocorticoid target tissues (kidney, parotid, and colon) and in nontarget tissues such as hippocampus and heart. In mineralocorticoid target tissues the receptors are selective for aldosterone in vivo because of the presence of the enzyme 11 beta-hydroxy-steroid dehydrogenase, which converts cortisol and corticosterone, but not aldosterone, to their 11-keto analogs. These analogs cannot bind to mineralocorticoid receptors.


High educational performance is a distinctive feature of bipolar disorder: a study on cognition in bipolar disorder, schizophrenia patients, relatives and controls.
Schizophrenia is associated with lower intelligence and poor educational performance relative to the general population. This is, to a lesser degree, also found in first-degree relatives of schizophrenia patients. It is unclear whether bipolar disorder I (BD-I) patients and their relatives have similar lower intellectual and educational performance as that observed in schizophrenia. This cross-sectional study investigated intelligence and educational performance in two outpatient samples [494 BD-I patients, 952 schizophrenia spectrum (SCZ) patients], 2231 relatives of BD-I and SCZ patients, 1104 healthy controls and 100 control siblings. Mixed-effects and regression models were used to compare groups on intelligence and educational performance. BD-I patients were more likely to have completed the highest level of education (odds ratio 1.88, 95% confidence interval 1.66-2.70) despite having a lower IQ compared to controls (β = -9.09, S.E. = 1.27, p < 0.001). In contrast, SCZ patients showed both a lower IQ (β = -15.31, S.E. = 0.86, p < 0.001) and lower educational levels compared to controls. Siblings of both patient groups had significantly lower IQ than control siblings, but did not differ on educational performance. IQ scores did not differ between BD-I parents and SCZ parents, but BD-I parents had completed higher educational levels. Although BD-I patients had a lower IQ than controls, they were more likely to have completed the highest level of education. This contrasts with SCZ patients, who showed both intellectual and educational deficits compared to healthy controls. Since relatives of BD-I patients did not demonstrate superior educational performance, our data suggest that high educational performance may be a distinctive feature of bipolar disorder patients.


Ameliorating effect of olive oil on fertility of male rats fed on genetically modified soya bean.
Genetically modified soya bean (GMSB) is a commercialized food. It has been shown to have adverse effects on fertility in animal trials. Extra virgin olive oil (EVOO) has many beneficial effects including anti-oxidant properties. The aim of this study is to elucidate if addition of EVOO ameliorates the adverse effects on reproductive organs of rats fed on GMSB containing diet. Forty adult male albino rats (150-180 g) of Sprague Dawley strain were separated into four groups of 10 rats each: Group 1 - control group fed on basal ration, Group 2 - fed on basal ration mixed with EVOO (30%), Group 3 - fed on basal ration mixed with GMSB (15%), and Group 4 - fed on basal ration mixed with GMSB (15%) and EVOO (30%). This feeding regimen was administered for 65 days. Blood samples were collected to analyze serum zinc, vitamin E, and testosterone levels. Histopathological and weight changes in sex organs were evaluated. GMSB diet reduced weight of testis (0.66±0.06 vs. 1.7±0.06, p<0.001), epididymis (0.489±0.03 vs. 0.7±0.03, p<0.001), prostate (0.04±0.009 vs. 0.68±0.04, p<0.001), and seminal vesicles (0.057±0.01 vs. 0.8±0.04, p<0.001). GMSB diet adversely affected sperm count (406±7.1 vs. 610±7.8, p<0.001), motility (p<0.001), and abnormality (p<0.001). GMSB diet also reduced serum zinc (p<0.05), vitamin E (p<0.05), and testosterone (p<0.05) concentrations. EVOO diet had no detrimental effect. Addition of EVOO to GMSB diet increased the serum zinc (p<0.05), vitamin E (p<0.05), and testosterone (p<0.05) levels and also restored the weights of testis (1.35±0.16 vs. 0.66±0.06, p<0.01), epididymis (0.614±0.13 vs. 0.489±0.03, p<0.001), prostate (0.291±0.09 vs. 0.04±0.009, p<0.001), seminal vesicle (0.516±0.18 vs. 0.057±0.01, p<0.001) along with sperm count (516±3.1 vs. 406±7.1, p<0.01), motility (p<0.01), and abnormality (p<0.05). EVOO ameliorates the adverse effects of GMSB on reproductive organs in adult male albino rats. This protective action of EVOO justifies its use against the oxidative damage induced by GMSB in reproductive organs.