Inflammatory bowel disease in primary sclerosing cholangitis: a robust yet changing relationship.
Primary sclerosing cholangitis (PSC) has a well-established association with inflammatory bowel disease (IBD) and may represent a distinctive phenotype. It is unknown whether changes in the clinical and endoscopic presentation of newly diagnosed IBD among patients with PSC might have occurred over time. Initial clinical and endoscopic presentations of IBD in PSC were studied for 2 different time periods: 1993 to 1997 (early cohort) compared with 2003 to 2007 (recent cohort). The baseline characteristics were similar in the 57 early cohort and 72 recent cohort patients. Compared with the recent cohort, alkaline phosphatase concentrations were higher in the early cohort (7.1 versus 2.6 × upper limit of normal, P = 0.0001). PSC was diagnosed before IBD in the recent cohort compared with the early cohort (50% versus 35%, P = 0.0009). The initial clinical and endoscopic presentations of IBD were similar in the 2 cohorts. The majority of patients had mild pancolitis, whereas rectal sparing and backwash ileitis were detected in one third and one fourth of patients, respectively. In addition, no differences in IBD outcomes or PSC characteristics were revealed. Immunomodulators and biological treatments were more commonly used in the recent cohort when compared with the early cohort (90% versus 56%, P = 0.03, and 13% versus 4%, P = 0.08, respectively). IBD in PSC has unique characteristics, and the clinical features of this unique presentation have remained stable over time. A shift in the timing of diagnosis of the 2 diseases has occurred in recent years, with PSC being more often diagnosed first.


Metabolism of the soyabean isoflavone daidzein by CYP1A2 and the extra-hepatic CYPs 1A1 and 1B1 affects biological activity.
Metabolism of the isoflavones daidzein and genistein, which may protect against some cancers, was studied using human liver microsomes and recombinant CYP isoforms. The detection of three, more polar metabolites of each isoflavone by RP-HPLC required NADPH, consistent with CYP-mediated metabolism. For different liver preparations, metabolite generation from daidzein showed a significant linear correlation with metabolite generation from genistein, indicating metabolism by the same CYP(s). The lowest rate of metabolism of both isoflavones was by the preparation with the lowest CYP1A2 activity. Metabolite peak areas were substantially and significantly reduced by the CYP1A2 inhibitor furafylline and to a lesser extent by the CYP2E1 inhibitor 4-methylpyrazole. Recombinant CYP1A2, but not CYP2E1, generated the metabolites of daidzein and genistein and recombinant CYP1A1 and CYP1B1, expressed at sites including the breast and prostate, were also active. The effects of two CYP-derived metabolites of daidzein, 6,7,4'-trihydroxyisoflavone and 7,3',4'-trihydroxyisoflavone, were studied in the MCF-7 human breast cancer cell line at a concentration (50 microM) at which daidzein induces an antiproliferative response. 7,3',4'-Trihydroxyisoflavone reduced total cell numbers to a greater extent than 6,7,4'-trihydroxyisoflavone or daidzein and increased cell death. Together, these data demonstrate proof of principle that CYP-mediated metabolism of daidzein can be an activation pathway. We conclude that CYP1A2 makes the major contribution to the hepatic metabolism of both daidzein and genistein and along with metabolism at sites of hormone-dependent tumours may enhance a cancer-protective effect of daidzein if sufficiently high concentrations are reached in target tissues.


Correlation of lactogenic receptor concentration in human breast cancer with estrogen receptor concentration.
The presence of receptors for lactogenic hormones in human breast cancer tissue has been documented previously, but the relationship between the expression of these receptors and estrogen receptor (ER) status has not been adequately studied. In this report, the specificity of 125I-human growth hormone (HGH) binding in both cultured human breast cancer cell lines and tumor biopsies was studied to establish that HGH was a suitable ligand for investigating lactogenic receptor concentration in these tissues. In addition, the relationship between specific binding of 125I-HGH and ER concentration in human breast cancer was investigated. Specific 125I-HGH binding to 14 breast cancer cell lines in long term culture and to membrane preparations (microsomal and plasma membrane fractions) from 31 breast cancer biopsy specimens was examined. Human prolactin and HGH were approximately equipotent in inhibiting binding of 125I-HGH to both cultured breast cancer cell lines and to membrane preparations from breast cancer biopsy specimens. Competitive inhibition experiments using lactogenic and somatogenic hormones established that the specificity of 125I-HGH binding to breast cancer biopsy material was similar to that of cultured breast cancer cell lines and similar to that reported for subprimate lactogenic receptors. Saturable, high-affinity (Ka = 0.53 to 2.33 nM-1), low-capacity (330 to 6560 sites/cell) growth hormone binding sites were found on each of the ER-positive cell lines, whereas no specific 125I-HGH binding to ER-negative cell monolayers was detected. When all cell lines were considered, a significant linear correlation (r = 0.745, p less than 0.001) between ER and lactogenic receptor concentrations was found. Significant specific 125I-HGH binding, greater than 1% of the total radioactivity added, was detected in 20 of 31 (65%) breast tumor biopsy specimens. The mean affinity and capacity of the lactogenic receptor as measured in 8 separate membrane preparations were Ka = 0.52 +/- 0.09 (S.E.) nM-1 and 255 +/- 85 fmol/mg protein. Membrane preparations from ER-negative tumors (less than 3 fmol ER/mg cytosol protein) bound significantly less 125I-HGH than did membrane preparations from ER-positive tumor biopsies (1.22 +/- 0.44 versus 3.21 +/- 0.56%, p less than 0.05). A significant linear correlation between specifically bound 125I-HGH and ER concentration (r = 0.412, p less than 0.02) was demonstrated in the 31 breast cancer biopsy specimens studied.(ABSTRACT TRUNCATED AT 400 WORDS)


Autoscopic phenomena.
Autoscopy is defined here as a visual experience where the subject sees an image of him/herself in external space, viewed from within his/her own physical body. This paper reviews the literature both historically and conceptually, and includes a quantitative study of accumulated cases. Cases published since 1935 and meeting the above definition for autoscopy (n = 53) were included, together with three personally-observed patients. A clinical protocol was completed for each case, including information about the autoscopic image. Cases were compared using non-parametric statistics on dichotomised variables. There were 38 men and 18 women, with a mean age of 39.5 years (range 13-78). Of the subjects, 33 (59%) had a neurological illness, most frequently epilepsy (18 cases). Right and left sided lesions were equally represented. Psychiatric disorder was often present (33 cases, 59%), most commonly delirium, depression or psychosis. The features of the images seen were diverse, but speaking images were associated with younger age, male sex, psychotic illness, longer duration of image, and hypnagogic/hypnopompic experiences. Autoscopy may arise from a convergence of several variables, including gender, personality factors, neurological and/or psychiatric disease, exhaustion and dissociation, whose interaction may override the normal inhibition of temporal lobe activity. A cognitive neuropsychological hypothesis is proposed, together with avenues for future research.


Diffusion-weighted imaging of breast cancer with the sensitivity encoding technique: analysis of the apparent diffusion coefficient value.
The usefulness of diffusion-weighted imaging (DWI) in the field of neuroradiology has been established. Despite its high contrast resolution, DWI has the disadvantages of susceptibility artifact and chemical shift artifact. We performed DWI of breast cancer with the sensitivity encoding (SENSE) technique. The subjects were 60 female patients with breast mass. All patients underwent MRI including SENSE-DWI and were diagnosed histologically. Of these patients, 55 were diagnosed with breast cancer and the remaining five were diagnosed with benign mass. The histological diagnoses of breast cancer were as follows: 39 cases of invasive ductal carcinoma (IDC); 11 cases of IDC with a predominant intraductal component and non IDC (pure or predominant NIDC); and five cases of special types of cancer. The MR system used was a Gyroscan Intera 1.5T (Philips Medical Systems). In addition to routine MRI for breast cancer, including contrast-enhanced dynamic, SENSE-DWI was obtained. The accuracy of the positional information of SENSE-DWI was visually compared with that of conventional images. The apparent diffusion coefficient (ADC) values of breast mass were analyzed with SENSE-DWI. The accuracy of positional information was adequate for diagnosing of all patients. The mean ADC value of breast cancer was 1.021x10(-3) mm2/s and that of benign mass was 1.488x10(-3) mm2/s (p=0.0002). The mean ADC value of IDC was 0.968x10(-3) mm2/s and that of pure or predominant NIDC was 1.218x10(-3) mm2/s (p=0.0011). SENSE-DWI was of sufficient quality to support diagnosis of breast mass. SENSE-DWI may permit the acquisition of more detailed information about lesions, including tumor cellularity, that is difficult to obtain with conventional techniques.


Aperiodic multilayers with enhanced reflectivity for extreme ultraviolet lithography.
We have developed novel aperiodic multilayers, covered by capping layers resistant to environmental attack, that offer superior performance for extreme ultraviolet lithography. We have designed these coatings using an optimization procedure based on an algorithm able to acquire domain knowledge inside the space of possible solutions. An integrated intensity increase of up to 2.18 times that obtained using standard periodic multilayers has been estimated. The aperiodic structures have minimal absorption in the topmost layers, which makes them especially insensitive to both the choice of capping layer material and any subsequent capping layer degradation due to oxidation or contamination. This property allows for the use of the most resilient capping layer materials available, thereby leading to a significantly improved lifetime. We have produced prototype capped aperiodic coatings and have measured their performance.


Comparison of ultrasound imaging in transverse median and parasagittal oblique planes for thoracic epidurals: A pilot study.
The use of ultrasound (US) scanning to assess the depth of epidural space to prevent neurological complications is established in current practice. In this study, we hypothesised that pre-puncture US scanning for estimating the depth of epidural space for thoracic epidurals is comparable between transverse median (TM) and paramedian sagittal oblique (PSO) planes. We performed pre-puncture US scanning in 32 patients, posted for open abdominal surgeries. The imaging was done to detect the depth of epidural space from skin (ultrasound depth [UD]) and needle insertion point, in parasagittal oblique plane in PSO group and transverse median plane in TM group. Subsequently, epidural space was localised through the predetermined insertion point by 'loss of resistance' technique and needle depth (ND) to the epidural space was marked. Correlation between the UD and actual ND was calculated and concordance correlation coefficient (CCC) was used to determine the degree of agreement between UD and ND in both the planes. The primary outcome, i.e., the comparison between UD and ND, done using Pearson correlation coefficient, was 0.99 in both PSO and TM groups, and the CCC was 0.93 (95% confidence interval [95% CI]: 0.81-0.97) and 0.90 (95% CI: 0.74-0.96) in PSO and TM groups respectively, which shows a strong positive association between UD and ND in both groups. The use of pre-puncture US scanning in both PSO and TM planes for estimating the depth of epidural space at the level of mid- and lower-thoracic spine is comparable.


Pan-erbB inhibition potentiates BRAF inhibitors for melanoma treatment.
The BRAF inhibitor vemurafenib is currently used for treating patients with BRAF V600E mutant melanoma. However, the responses to vemurafenib are generally partial and of relatively short duration. Recent evidence suggests that activation of the epidermal growth factor receptor (EGFR)/erbB signaling pathway may be responsible for the development of BRAF inhibitor resistance in melanoma patients. In this study, we characterized the erbB family of receptors and ligands in melanoma cell lines and examined whether targeting both BRAF and erbB provided enhanced antitumor activity in BRAF mutant melanoma. Variable levels of erbB2, erbB3, and truncated erbB4 were expressed in both BRAF wildtype and mutant melanoma cells with no significant differences between wildtype and mutant lines. EGFR was rarely expressed. Neuregulin 3 and neuregulin 4 were the major erbB ligands released by melanoma cells. Multi-erbB targeting with the irreversible tyrosine kinase inhibitor canertinib exerted a more effective growth inhibitory effect in both BRAF wildtype and mutant melanoma cells compared with the single-erbB or dual-erbB targeting inhibitors, gefitinib, erlotinib, and lapatinib. Canertinib inhibited both EGF-induced and neuregulin 1-induced erbB downstream signaling in both mutant and wildtype cell lines. However, canertinib induced apoptosis and sub-G1 arrest only in mutant cells. Canertinib statistically increased the antiproliferative effects of vemurafenib in the BRAF mutant melanoma cell lines while little or no enhanced effect was observed with the combination treatment in the wildtype cell lines. A combined inhibition strategy targeting BRAF together with multiple erbB family kinases is potentially beneficial for treating BRAF V600E mutant melanoma. Wildtype BRAF melanoma may also benefit from a multi-erbB kinase inhibitor.


High Ca2+ concentrations induce a low activity mode and reveal Ca2(+)-independent long shut intervals in BK channels from rat muscle.
1. Large-conductance calcium-activated K+ channels (BK channels) often display long closed intervals at higher levels of Ca2+. To gain further insight into possible mechanisms for these intervals, currents were recorded from single BK channels, using the patch clamp technique, from patches of membrane excised from primary cultures of rat skeletal muscle. 2. High intracellular calcium concentrations ([Ca2+]i; 10-1000 microM) induced a low activity mode and revealed isolated long shut intervals. Neither of these phenomena were due to the Ba2+ that typically contaminates reagent grade salts. 3. The low activity mode was characterized by typically single brief open intervals with mean durations of 0.1 ms, separated by long shut intervals with mean durations of 100 ms. The very low open probability of about 0.001 during the low activity mode would make a sojourn to this mode functionally equivalent to a sojourn to an inactive state. The durations of sojourns in the low activity mode were exponentially distributed, with the mean durations ranging from about 1 s in 10 microM Ca(i)2+, to 4.5 s in 1000 microM Ca(i)2+. With increased filtering, the brief open intervals would escape detection so that a sojourn to the low activity mode would appear as a single shut interval. A typical channel spent less than 5% of its time in the low activity mode for [Ca2+]i < 10 microM. This increased to about 30% for [Ca2+]i > 100-1000 microM. A kinetic model with three closed states and two open states could approximate the gating of the low activity mode. 4. The isolated long shut intervals were not from the low activity mode, suggesting a different underlying mechanism. Their frequency of occurrence of about 0.3 s-1 did not increase with increasing [Ca2+]i, indicating that they did not arise from a slow Ca2+ block. Their durations were exponentially distributed, with a mean of 127 ms, which was independent of [Ca2+]i, suggesting that a single Ca(2+)-independent closed state or block underlies the isolated long shut intervals. At higher [Ca2+]i, up to 60% of the shut time could be spent in the isolated long shut intervals. 5. These observations suggest that activation of BK channels by high [Ca2+]i can be limited by sojourns to a low activity mode and also by isolated long shut intervals, two additional phenomena that will have to be accounted for in the gating of BK channels.


The Edinburgh Feeding Evaluation in Dementia Scale: A Longitudinal Study in Nursing Home Residents.
The Edinburgh Feeding Evaluation in Dementia (EdFED) scale has been shown to have good psychometric properties using a range of methods including Mokken scaling. We aimed to study the Italian version of the EdFED using Mokken scaling. Data were gathered at 7 time points from 401 nursing home residents affected by dementia in the course of a 6-month intervention study using analysis of variance, Mokken scaling, and person-item fit statistics. The properties of the EdFED-I scale were stable over the course of the study with 4 items showing invariant item ordering at all time points. Some items behaved differently at different levels of difficulty in the scale and also depending on the mean level of feeding difficulty. The test information function showed a dip in the mid-range of difficulty scores.


Characterization of AmiBA2446, a novel bacteriolytic enzyme active against Bacillus species.
There continues to be a need for developing efficient and environmentally friendly treatments for Bacillus anthracis, the causative agent of anthrax. One emerging approach for inactivation of vegetative B. anthracis is the use of bacteriophage endolysins or lytic enzymes encoded by bacterial genomes (autolysins) with highly evolved specificity toward bacterium-specific peptidoglycan cell walls. In this work, we performed in silico analysis of the genome of Bacillus anthracis strain Ames, using a consensus binding domain amino acid sequence as a probe, and identified a novel lytic enzyme that we termed AmiBA2446. This enzyme exists as a homodimer, as determined by size exclusion studies. It possesses N-acetylmuramoyl-l-alanine amidase activity, as determined from liquid chromatography-mass spectrometry (LC-MS) analysis of muropeptides released due to the enzymatic digestion of peptidoglycan. Phylogenetic analysis suggested that AmiBA2446 was an autolysin of bacterial origin. We characterized the effects of enzyme concentration and phase of bacterial growth on bactericidal activity and observed close to a 5-log reduction in the viability of cells of Bacillus cereus 4342, a surrogate for B. anthracis. We further tested the bactericidal activity of AmiBA2446 against various Bacillus species and demonstrated significant activity against B. anthracis and B. cereus strains. We also demonstrated activity against B. anthracis spores after pretreatment with germinants. AmiBA2446 enzyme was also stable in solution, retaining its activity after 4 months of storage at room temperature.


Sex in cheese: evidence for sexuality in the fungus Penicillium roqueforti.
Although most eukaryotes reproduce sexually at some moment of their life cycle, as much as a fifth of fungal species were thought to reproduce exclusively asexually. Nevertheless, recent studies have revealed the occurrence of sex in some of these supposedly asexual species. For industrially relevant fungi, for which inoculums are produced by clonal-subcultures since decades, the potentiality for sex is of great interest for strain improvement strategies. Here, we investigated the sexual capability of the fungus Penicillium roqueforti, used as starter for blue cheese production. We present indirect evidence suggesting that recombination could be occurring in this species. The screening of a large sample of strains isolated from diverse substrates throughout the world revealed the existence of individuals of both mating types, even in the very same cheese. The MAT genes, involved in fungal sexual compatibility, appeared to evolve under purifying selection, suggesting that they are still functional. The examination of the recently sequenced genome of the FM 164 cheese strain enabled the identification of the most important genes known to be involved in meiosis, which were found to be highly conserved. Linkage disequilibria were not significant among three of the six marker pairs and 11 out of the 16 possible allelic combinations were found in the dataset. Finally, the detection of signatures of repeat induced point mutations (RIP) in repeated sequences and transposable elements reinforces the conclusion that P. roqueforti underwent more or less recent sex events. In this species of high industrial importance, the induction of a sexual cycle would open the possibility of generating new genotypes that would be extremely useful to diversify cheese products.


Ecological momentary assessment of urban adolescents' technology use and cravings for unhealthy snacks and drinks: differences by ethnicity and sex.
Adolescents' technology use is generally associated with food cravings, but it is not clear whether specific types of technology elicit particular types of cravings or whether personal characteristics play a role in these associations. We examined whether momentary associations between four technology types (ie, television, video games, computer messaging, and phone messaging) and cravings for unhealthy snack foods and sweetened drinks were moderated by youths' sex, ethnicity, body mass index, and age. Urban adolescents (N=158) aged 14 to 17 years provided momentary information about their technology use and food cravings during the course of 1 week and completed survey reports of their personal characteristics. We used multilevel modeling to determine momentary associations and interactions. Non-Hispanic adolescents showed stronger associations between television exposure and cravings for sweet snacks, salty snacks, and sweetened drinks. Being Hispanic was associated with stronger associations between phone messaging and cravings for sweet snacks, salty snacks, and sweetened drinks. Males showed stronger associations between video game use and salty snack cravings. As the public health field continues to monitor the effects of technology use on adolescents' eating and overall health, it will be important to determine the extent to which these groups are differentially affected by different forms of technology.


A smart medication recommendation model for the electronic prescription.
The report from the Institute of Medicine, To Err Is Human: Building a Safer Health System in 1999 drew a special attention towards preventable medical errors and patient safety. The American Reinvestment and Recovery Act of 2009 and federal criteria of 'Meaningful use' stage 1 mandated e-prescribing to be used by eligible providers in order to access Medicaid and Medicare incentive payments. Inappropriate prescribing has been identified as a preventable cause of at least 20% of drug-related adverse events. A few studies reported system-related errors and have offered targeted recommendations on improving and enhancing e-prescribing system. This study aims to enhance efficiency of the e-prescribing system by shortening the medication list, reducing the risk of inappropriate selection of medication, as well as in reducing the prescribing time of physicians. 103.48 million prescriptions from Taiwan's national health insurance claim data were used to compute Diagnosis-Medication association. Furthermore, 100,000 prescriptions were randomly selected to develop a smart medication recommendation model by using association rules of data mining. The important contribution of this model is to introduce a new concept called Mean Prescription Rank (MPR) of prescriptions and Coverage Rate (CR) of prescriptions. A proactive medication list (PML) was computed using MPR and CR. With this model the medication drop-down menu is significantly shortened, thereby reducing medication selection errors and prescription times. The physicians will still select relevant medications even in the case of inappropriate (unintentional) selection.


ICAM-1-mediated, Src- and Pyk2-dependent vascular endothelial cadherin tyrosine phosphorylation is required for leukocyte transendothelial migration.
Leukocyte transendothelial migration (TEM) has been modeled as a multistep process beginning with rolling adhesion, followed by firm adhesion, and ending with either transcellular or paracellular passage of the leukocyte across the endothelial monolayer. In the case of paracellular TEM, endothelial cell (EC) junctions are transiently disassembled to allow passage of leukocytes. Numerous lines of evidence demonstrate that tyrosine phosphorylation of adherens junction proteins, such as vascular endothelial cadherin (VE-cadherin) and beta-catenin, correlates with the disassembly of junctions. However, the role of tyrosine phosphorylation in the regulation of junctions during leukocyte TEM is not completely understood. Using human leukocytes and EC, we show that ICAM-1 engagement leads to activation of two tyrosine kinases, Src and Pyk2. Using phospho-specific Abs, we show that engagement of ICAM-1 induces phosphorylation of VE-cadherin on tyrosines 658 and 731, which correspond to the p120-catenin and beta-catenin binding sites, respectively. These phosphorylation events require the activity of both Src and Pyk2. We find that inhibition of endothelial Src with PP2 or SU6656 blocks neutrophil transmigration (71.1 +/- 3.8% and 48.6 +/- 3.8% reduction, respectively), whereas inhibition of endothelial Pyk2 also results in decreased neutrophil transmigration (25.5 +/- 6.0% reduction). Moreover, overexpression of the nonphosphorylatable Y658F or Y731F mutants of VE-cadherin impairs transmigration of neutrophils compared with overexpression of wild-type VE-cadherin (32.7 +/- 7.1% and 38.8 +/- 6.5% reduction, respectively). Our results demonstrate that engagement of ICAM-1 by leukocytes results in tyrosine phosphorylation of VE-cadherin, which is required for efficient neutrophil TEM.


Different storing and processing conditions of human lymphocytes do not alter P-glycoprotein rhodamine 123 efflux.
P-glycoprotein (Pgp), a protein codified by Multi Drug Resistance (MDR1) gene, has a detoxifying function and might influence the toxicity and pharmacokinetics and pharmacodynamics of drugs. Sampling strategies to improve Pgp studies could be useful to optimize the sensitivity and the reproducibility of efflux assays. This study aimed to compare Pgp expression and efflux activity by measuring Rhodamine123 (Rh123) retention in lymphocytes stored under different conditions, in order to evaluate the potential utility of any of the storing conditions in Pgp functionality. Our results show no change in protein expression of Pgp by confocal studies and Western blotting, nor changes at the mRNA level (qRT-PCR). No differences in Rh123 efflux by Pgp activity assays were found between fresh and frozen lymphocytes after 24 hours of blood extraction, using either of the two Pgp specific inhibitors (VP and PSC833). Different working conditions in the 24 hours post blood extraction do not affect Rh123 efflux. These results allow standardization of Pgp activity measurement in different individuals with different timing of blood sampling and in different geographic areas.


Poststroke rehabilitation: outcomes and reimbursement of inpatient rehabilitation facilities and subacute rehabilitation programs.
To assess whether poststroke rehabilitation outcomes and reimbursement for Medicare beneficiaries differ across inpatient rehabilitation facilities (IRFs) and skilled nursing facility (SNF) subacute rehabilitation programs. Clinical data were linked with Medicare claims for 58,724 Medicare beneficiaries with a recent stroke who completed treatment in 1996 or 1997 in IRFs and subacute rehabilitation SNFs that subscribed to the Uniform Data System for Medical Rehabilitation. Outcome measures were discharge destination, discharge FIM ratings and Medicare Part A reimbursement during the institutional stay. IRF patients that were more likely to have a community-based discharge, compared with rehabilitation SNF patients, were patients with mild motor disabilities and FIM cognitive ratings of 23 or greater (adjusted odds ratio [AOR]=2.19; 95% CI: 1.52 to 3.14), patients with moderate motor disabilities (AOR=1.98; 95% CI: 1.49 to 2.61), patients with significant motor disabilities (AOR=1.26; 95% CI: 1.01 to 1.57) and patients younger than 82 with severe motor disabilities (AOR=1.43; 95% CI: 1.25 to 1.64). IRF patients with significant and severe motor disabilities achieved greater motor function of 2 or more FIM units compared with rehabilitation SNF patients. Medicare Part A payments for IRFs were higher than rehabilitation SNF payments across all subgroups. For most patients, poststroke rehabilitation in the more costly and intensive IRFs resulted in higher functional outcomes compared with care in a SNF-based rehabilitation program. IRF and SNF outcomes were similar for patients with minimal motor disabilities and patients with mild motor disabilities and significant cognitive disabilities. Cost-effectiveness analyses require considering the costs of the full episode of care.


Lexical segmentation and vocabulary growth in early language acquisition.
The identification of appropriate lexical segmentations of the speech signal constitutes a problem for the language learner and the child language researcher alike. Articulatory precision and fluency criteria for identifying formulaic expressions, sub-lexical forms and target lexemes in linguistic productions are defined and applied to the analysis of two Danish children's language development between the ages of 1;0 and 2;0. The results of this analysis are compared to the results of applying standard distributional and frequency criteria in the tabulation of mean length of utterance and vocabulary profiles for both standard and non-standard lexical segmentations. It is argued that although the two methods yield converging profiles of development during the latter part of the period studied, articulatory precision and fluency criteria offer a more powerful tool for identifying alternative segmentation strategies in early language acquisition. Profiles of vocabulary development for these two children suggest that the solution to the segmentation problem may be an important trigger for their vocabulary spurts.


Phylogeny-function analysis of (meta)genomic libraries: screening for expression of ribosomal RNA genes by large-insert library fluorescent in situ hybridization (LIL-FISH).
We assessed the utility of fluorescent in situ hybridization (FISH) in the screening of clone libraries of (meta)genomic or environmental DNA for the presence and expression of bacterial ribosomal RNA (rRNA) genes. To establish proof-of-principle, we constructed a fosmid-based library in Escherichia coli of large-sized genomic DNA fragments of the mycophagous soil bacterium Collimonas fungivorans, and hybridized 768 library clones with the Collimonas-specific fluorescent probe CTE998-1015. Critical to the success of this approach (which we refer to as large-insert library FISH or LIL-FISH) was the ability to induce fosmid copy number, the exponential growth status of library clones in the FISH assay and the use of a simple pooling strategy to reduce the number of hybridizations. Twelve out of 768 E. coli clones were suspected to harbour and express Collimonas 16S rRNA genes based on their hybridization to CTE998-1015. This was confirmed by the finding that all 12 clones were also identified in an independent polymerase chain reaction-based screening of the same 768 clones using a primer set for the specific detection of Collimonas 16S ribosomal DNA (rDNA). Fosmids isolated from these clones were grouped by restriction analysis into two distinct contigs, confirming that C. fungivorans harbours at least two 16S rRNA genes. For one contig, representing 1-2% of the genome, the nucleotide sequence was determined, providing us with a narrow but informative view of Collimonas genome structure and content.


Limiting factors in single particle cryo electron tomography.
Modern methods of cryo electron microscopy and tomography allow visualization of protein nanomachines in their native state at the nanometer scale. Image processing methods including sub-volume averaging applied to repeating macromolecular elements within tomograms allow exploring their structures within the native context of the cell, avoiding the need for protein isolation and purification. Today, many different data acquisition protocols and software solutions are available to researchers to determine average structures of macromolecular complexes and potentially to classify structural intermediates. Here, we list the density maps reported in the literature, and analyze each structure for the chosen instrumental settings, sample conditions, main processing steps, and obtained resolution. We present conclusions that identify factors currently limiting the resolution gained by this approach.


Mating disruption of Planococcus ficus (Hemiptera: Pseudococcidae) in vineyards using reservoir pheromone dispensers.
Mating disruption field experiments to control the vine mealybug, Planococcus ficus (Signoret) (Hemiptera: Pseudococcidae), were carried out in 2008 and 2009 in two commercial vineyards in Sardinia (Italy). The effectiveness of mating disruption was evaluated by testing reservoir dispensers loaded with 100 mg (62.5 g/ha) and 150 mg (93.8 g/ha) of the sex pheromone in 2008 and 2009, respectively. The number of males captured in pheromone traps, the P. ficus population density and age structure, the parasitism rate, the percentage of ovipositing females, and the crop damage were compared between disrupted and untreated plots. In both field trials, the number of males captured in mating disruption plots was significantly reduced by 86% and 95%, respectively. Mating disruption at the initial dose of 62.5 g/ha of active ingredient gave inconclusive results, whereas the dose of 93.8 g/ha significantly lowered the mealybug density and modified the age structure, which showed a lower percentage of ovipositing females and a higher proportion of preovipositing females. Mating disruption did not affect negatively the parasitism rate, which was higher in the disrupted than in the control plots (>1.5-fold). Crop damage at harvest was very low in both field trials and did not differ between treatments. Mating disruption was effective in wide plots protected with dispensers loaded with 150 mg of the sex pheromone, showing its potential to be included in the overall integrated control programs in Mediterranean wine-growing regions.


TDP-43 regulates global translational yield by splicing of exon junction complex component SKAR.
TDP-43 is linked to neurodegenerative diseases including frontotemporal dementia and amyotrophic lateral sclerosis. Mostly localized in the nucleus, TDP-43 acts in conjunction with other ribonucleoproteins as a splicing co-factor. Several RNA targets of TDP-43 have been identified so far, but its role(s) in pathogenesis remains unclear. Using Affymetrix exon arrays, we have screened for the first time for splicing events upon TDP-43 knockdown. We found alternative splicing of the ribosomal S6 kinase 1 (S6K1) Aly/REF-like target (SKAR) upon TDP-43 knockdown in non-neuronal and neuronal cell lines. Alternative SKAR splicing depended on the first RNA recognition motif (RRM1) of TDP-43 and on 5'-GA-3' and 5'-UG-3' repeats within the SKAR pre-mRNA. SKAR is a component of the exon junction complex, which recruits S6K1, thereby facilitating the pioneer round of translation and promoting cell growth. Indeed, we found that expression of the alternatively spliced SKAR enhanced S6K1-dependent signaling pathways and the translational yield of a splice-dependent reporter. Consistent with this, TDP-43 knockdown also increased translational yield and significantly increased cell size. This indicates a novel mechanism of deregulated translational control upon TDP-43 deficiency, which might contribute to pathogenesis of the protein aggregation diseases frontotemporal dementia and amyotrophic lateral sclerosis.


A Diagnostic Marker to Discriminate Childhood Apraxia of Speech From Speech Delay: III. Theoretical Coherence of the Pause Marker with Speech Processing Deficits in Childhood Apraxia of Speech.
Previous articles in this supplement described rationale for and development of the pause marker (PM), a diagnostic marker of childhood apraxia of speech (CAS), and studies supporting its validity and reliability. The present article assesses the theoretical coherence of the PM with speech processing deficits in CAS. PM and other scores were obtained for 264 participants in 6 groups: CAS in idiopathic, neurogenetic, and complex neurodevelopmental disorders; adult-onset apraxia of speech (AAS) consequent to stroke and primary progressive apraxia of speech; and idiopathic speech delay. Participants with CAS and AAS had significantly lower scores than typically speaking reference participants and speech delay controls on measures posited to assess representational and transcoding processes. Representational deficits differed between CAS and AAS groups, with support for both underspecified linguistic representations and memory/access deficits in CAS, but for only the latter in AAS. CAS-AAS similarities in the age-sex standardized percentages of occurrence of the most frequent type of inappropriate pauses (abrupt) and significant differences in the standardized occurrence of appropriate pauses were consistent with speech processing findings. Results support the hypotheses of core representational and transcoding speech processing deficits in CAS and theoretical coherence of the PM's pause-speech elements with these deficits.


Plant cell wall imaging by metabolic click-mediated labelling of rhamnogalacturonan II using azido 3-deoxy-D-manno-oct-2-ulosonic acid.
In plants, 3-deoxy-d-manno-oct-2-ulosonic acid (Kdo) is a monosaccharide that is only found in the cell wall pectin, rhamnogalacturonan-II (RG-II). Incubation of 4-day-old light-grown Arabidopsis seedlings or tobacco BY-2 cells with 8-azido 8-deoxy Kdo (Kdo-N3 ) followed by coupling to an alkyne-containing fluorescent probe resulted in the specific in muro labelling of RG-II through a copper-catalysed azide-alkyne cycloaddition reaction. CMP-Kdo synthetase inhibition and competition assays showing that Kdo and D-Ara, a precursor of Kdo, but not L-Ara, inhibit incorporation of Kdo-N3 demonstrated that incorporation of Kdo-N3 occurs in RG-II through the endogenous biosynthetic machinery of the cell. Co-localisation of Kdo-N3 labelling with the cellulose-binding dye calcofluor white demonstrated that RG-II exists throughout the primary cell wall. Additionally, after incubating plants with Kdo-N3 and an alkynated derivative of L-fucose that incorporates into rhamnogalacturonan I, co-localised fluorescence was observed in the cell wall in the elongation zone of the root. Finally, pulse labelling experiments demonstrated that metabolic click-mediated labelling with Kdo-N3 provides an efficient method to study the synthesis and redistribution of RG-II during root growth.


One-step design of a stable variant of the malaria invasion protein RH5 for use as a vaccine immunogen.
Many promising vaccine candidates from pathogenic viruses, bacteria, and parasites are unstable and cannot be produced cheaply for clinical use. For instance, Plasmodium falciparum reticulocyte-binding protein homolog 5 (PfRH5) is essential for erythrocyte invasion, is highly conserved among field isolates, and elicits antibodies that neutralize in vitro and protect in an animal model, making it a leading malaria vaccine candidate. However, functional RH5 is only expressible in eukaryotic systems and exhibits moderate temperature tolerance, limiting its usefulness in hot and low-income countries where malaria prevails. Current approaches to immunogen stabilization involve iterative application of rational or semirational design, random mutagenesis, and biochemical characterization. Typically, each round of optimization yields minor improvement in stability, and multiple rounds are required. In contrast, we developed a one-step design strategy using phylogenetic analysis and Rosetta atomistic calculations to design PfRH5 variants with improved packing and surface polarity. To demonstrate the robustness of this approach, we tested three PfRH5 designs, all of which showed improved stability relative to wild type. The best, bearing 18 mutations relative to PfRH5, expressed in a folded form in bacteria at >1 mg of protein per L of culture, and had 10-15 °C higher thermal tolerance than wild type, while also retaining ligand binding and immunogenic properties indistinguishable from wild type, proving its value as an immunogen for a future generation of vaccines against the malaria blood stage. We envision that this efficient computational stability design methodology will also be used to enhance the biophysical properties of other recalcitrant vaccine candidates from emerging pathogens.


Solution structure of polymerase mu's BRCT Domain reveals an element essential for its role in nonhomologous end joining.
The solution structure and dynamics of the BRCT domain from human DNA polymerase mu, implicated in repair of chromosome breaks by nonhomologous end joining (NHEJ), has been determined using NMR methods. BRCT domains are typically involved in protein-protein interactions between factors required for the cellular response to DNA damage. The pol mu BRCT domain is atypical in that, unlike other reported BRCT structures, the pol mu BRCT is neither part of a tandem grouping, nor does it appear to form stable homodimers. Although the sequence of the pol mu BRCT domain has some unique characteristics, particularly the presence of >10% proline residues, it forms the characteristic alphabetaalpha sandwich, in which three alpha helices are arrayed around a central four-stranded beta-sheet. The structure of helix alpha1 is characterized by two solvent-exposed hydrophobic residues, F46 and L50, suggesting that this element may play a role in mediating interactions of pol mu with other proteins. Consistent with this argument, mutation of these residues, as well as the proximal, conserved residue R43, specifically blocked the ability of pol mu to efficiently work together with NHEJ factors Ku and XRCC4-ligase IV to join noncomplementary ends together in vitro. The structural, dynamic, and biochemical evidence reported here identifies a functional surface in the pol mu BRCT domain critical for promoting assembly and activity of the NHEJ machinery. Further, the similarity between the interaction regions of the BRCT domains of pol mu and TdT support the conclusion that they participate in NHEJ as alternate polymerases.


Effects of Levothyroxine Therapy on Pregnancy Outcomes in Women with Subclinical Hypothyroidism.
Subclinical hypothyroidism (SCH) has been associated with increased risk of adverse pregnancy outcomes in some, but not all, studies. Uncertainty remains regarding the impact of levothyroxine (LT4) therapy on improving health outcomes in pregnant women with SCH. The objective of this study was to assess the potential benefits of LT4 therapy in pregnant women with SCH. The medical records were reviewed of pregnant women with SCH, defined as an elevated serum thyrotropin (TSH) of >2.5 mIU/L for the 1st trimester or >3 mIU/L for the 2nd and 3rd trimesters, but ≤10 mIU/L. Pregnant women were divided into two groups depending on whether they received LT4 (group A) or not (group B). Pregnancy loss and other pre-specified adverse outcomes were evaluated during follow-up. There were 82 women in group A and 284 in group B. Group A had a higher body mass index (p = 0.04) and a higher serum TSH level (p < 0.0001) compared with group B. Group A had fewer pregnancies lost (n = 5 [6.1%] vs. n = 25 [8.8%]; p = 0.12), low birth weight (LBW) offspring (1.3% vs. 10%; p < 0.001), and no neonates with a five-minute Apgar score ≤7 (0% vs. 7%; p < 0.001) compared with group B. Other pregnancy-related adverse outcomes were similar between the two groups. Inferences remained unchanged after considering different models to adjust for potential predictors of outcome. LT4 therapy is associated with a decreased risk of LBW and a low Apgar score among women with SCH. This association awaits confirmation in randomized trials before the widespread use of LT4 therapy in pregnant women with SCH.


Melleolides impact fungal translation via elongation factor 2.
Melleolides from the honey mushroom Armillaria mellea represent a structurally diverse group of polyketide-sesquiterpene hybrids. Among various bioactivites, melleolides show antifungal effects against Aspergillus and other fungi. This bioactivity depends on a Δ2,4-double bond present in dihydroarmillylorsellinate (DAO) or arnamial, for example. Yet, the mode of action of Δ2,4-unsaturated, antifungal melleolides has been unknown. Here, we report on the molecular target of DAO in the fungus Aspergillus nidulans. Using a combination of synthetic chemistry to create a DAO-labelled probe, protein pulldown assays, MALDI-TOF-based peptide analysis and western blotting, we identify the eukaryotic translation elongation factor 2 (eEF2) as a binding partner of DAO. We confirm the inhibition of protein biosynthesis in vivo with an engineered A. nidulans strain producing the red fluorescent protein mCherry. Our work suggests a binding site dissimilar from that of the protein biosynthesis inhibitor sordarin, and highlights translational elongation as a valid antifungal drug target.


Prioritizing maternal and child health in independent South Sudan.
With its independence secured on 9th July 2011, the Republic of South Sudan faces a daunting task to improve public health and primary care in one of the poorest countries in the world. Very high maternal and child mortality rates must be a major concern for the new national government and for the many international agencies working in the country. Poor maternal health outcomes are primarily due to poor prenatal, delivery and post natal care services in health facilities, coupled with low literacy, widespread poverty, and poor nutrition among the general population. Child mortality is the result of widespread malnutrition, pneumonia, malaria, vaccine preventable diseases and diarrheal diseases. National responses to HIV and AIDS with international assistance have been encouraging with relatively low rates of infection. This paper explores barriers and identifies opportunities available to work toward achieving the targets for Millennium Development Goals (MDGs) 5 and 4 to reduce maternal mortality from its current rate of 2,054 deaths per 100,000 live births, and child mortality (currently 135 deaths per 1,000 live births) respectively in the new nation. National and international organizations have a social responsibility to mobilize efforts to focus on maternal, child health and nutrition issues targeting the worst affected regions for improving access to primary care and obstetrical services. Initiatives are needed to build up community access to primary care with a well supervised community health workers program, as well as training mid level management capacity with higher levels of funding from national and international sources to promote public health than current in the new republic.


Do antibacterial mouthrinses affect bacteraemia in third molar surgery? A pilot study.
The aim of this pilot study was to evaluate the effects of mouthrinses containing 7.5% povidone iodine and 0.2% chlorhexidine on bacteraemia following impacted third molar surgery. Thirty-four patients were enrolled in this study. Patients in the first group were asked to rinse their mouth with the mouthrinse containing 7.5% povidone iodine, patients in the second group were asked to rinse with the mouthrinse containing 0.2% chlorhexidine and patients in the third group were asked to rinse with 0.9% NaCl (sterile saline) solution. All rinses were used for one minute preoperatively. Peripheral venous blood samples were collected at baseline (preoperatively), 1 and 15 minutes after the completion of surgical tooth removal. Each blood sample was divided in two, placed in aerobic and anaerobic culture bottles and processed for microbiological examination. Bactaeremia was detected in 33% of the povidone iodine group, 33% of the chlorhexidine group and 50% of the control group. Isolated bacteria were 58% anaerobes and predominantly 92%Streptococcus species. Incidence of bacteraemia was reduced with chlorhexidine and povidone iodine mouthrinses in third molar surgery, although the difference was not statistically significant (p > 0.05). Bacteraemia was reduced with antibacterial mouthrinses in third molar surgery. The results of this study should be confirmed with further studies conducted on a larger patient population and with different antibacterial mouthrinses.


Properties of integral membrane protein structures: derivation of an implicit membrane potential.
Distributions of each amino acid in the trans-membrane domain were calculated as a function of the membrane normal using all currently available alpha-helical membrane protein structures with resolutions better than 4 A. The results were compared with previous sequence- and structure-based analyses. Calculation of the average hydrophobicity along the membrane normal demonstrated that the protein surface in the membrane domain is in fact much more hydrophobic than the protein core. While hydrophobic residues dominate the membrane domain, the interfacial regions of membrane proteins were found to be abundant in the small residues glycine, alanine, and serine, consistent with previous studies on membrane protein packing. Charged residues displayed nonsymmetric distributions with a preference for the intracellular interface. This effect was more prominent for Arg and Lys resulting in a direct confirmation of the positive inside rule. Potentials of mean force along the membrane normal were derived for each amino acid by fitting Gaussian functions to the residue distributions. The individual potentials agree well with experimental and theoretical considerations. The resulting implicit membrane potential was tested on various membrane proteins as well as single trans-membrane alpha-helices. All membrane proteins were found to be at an energy minimum when correctly inserted into the membrane. For alpha-helices both interfacial (i.e. surface bound) and inserted configurations were found to correspond to energy minima. The results demonstrate that the use of trans-membrane amino acid distributions to derive an implicit membrane representation yields meaningful residue potentials.


Role of metastasis-associated lung adenocarcinoma transcript-1 (MALAT-1) in pancreatic cancer.
Metastasis-associated lung adenocarcinoma transcript-1 (MALAT-1) is a long non-coding RNA (lncRNA) that is a negative prognostic factor for patients with pancreatic cancer and several other tumors. In this study, we show that knockdown of MALAT-1 in Panc1 and other pancreatic cancer cell lines decreases cell proliferation, survival and migration. We previously observed similar results for the lncRNAs HOTTIP and HOTAIR in Panc1 cells; however, RNAseq comparison of genes regulated by MALAT-1 shows minimal overlap with HOTTIP/HOTAIR-regulated genes. Analysis of changes in gene expression after MALAT-1 knockdown shows that this lncRNA represses several tumor suppressor-like genes including N-myc downregulated gene-1 (NDRG-1), a tumor suppressor in pancreatic cancer that is also corepressed by EZH2 (a PRC2 complex member). We also observed that Specificity proteins Sp1, Sp3 and Sp4 are overexpressed in Panc1 cells and Sp knockdown or treatment with small molecules that decrease Sp proteins expression also decrease MALAT-1 expression. We also generated Kras-overexpressing p53L/L;LSL-KrasG12DL/+;p48Cre+/- (p53L/L/KrasG12D) and p53L/+;LSLKrasG12DL/+;p48Cre+/- (p53L/+/KrasG12D) mice which are p53 homo- and heterozygous, respectively. These mice rapidly develop pancreatic ductal adenocarcinoma-like tumors and were crossed with MALAT-1-/- mice. We observed that the loss of one or two MALAT-1 alleles in these Ras overexpressing mice does not significantly affect the time to death; however, the loss of MALAT-1 in the p53-/+ (heterozygote) mice slightly increases their lifespan.


Dietary glycotoxins: inhibition of reactive products by aminoguanidine facilitates renal clearance and reduces tissue sequestration.
Evidence indicates that the metabolic turnover of food-derived reactive orally absorbed advanced glycation end products (AGEs) or glycotoxins (GTs) is delayed, possibly contributing to the tissue damage induced by endogenous AGEs, especially in patients with diabetes and kidney disease. The aim of this study was to explore whether pharmacologic inhibition of dietary AGE bioreactivity by aminoguanidine (AG) can improve turnover and renal excretion of these substances. Normal Sprague-Dawley rats were fed single-labeled [14C]AGE-ovalbumin, double-labeled [14C-125I]AGE-ovalbumin, or control 125I-labeled ovalbumin diet plus free [14C]glucose, with or without AG (0.2% in water). [14C]AGE- and 125I-labeled peptide-associated radioactivity (RA) were compared with AGE immunoreactivity (by enzyme-linked immunosorbent assay) in tissues, serum, and 72-h urine samples. The effect of AG on dietary AGE bioreactivity was assessed by monitoring the inhibition of covalent complex formation between fibronectin (FN) peptide fragments and serum components, after a meal of labeled dietary AGE with or without AG. The radiolabeled AGE diet produced serum absorption and urinary excretion peaks kinetically distinct from those of free [14C]glucose or [125I]ovalbumin. Some 26% of the orally absorbed AGE-ovalbumin was excreted in the urine, whereas after AG treatment, urinary excre-tion of dietary AGEs increased markedly (to >50% of absorbed). More than 60% of tissue-bound RA was found covalently deposited in kidneys and liver, whereas after treatment with AG, tissue AGE deposits were reduced to <15% of the amount found in untreated AGE-fed controls. Sera enriched for dietary GTs formed covalently linked complexes with FN, a process completely inhibitable by AG cotreatment. Amelioration of dietary GT bioreactivity by AG improves renal elimination and prevents tissue deposition of food GTs. This may afford a novel and potentially protective use of AG against excessive tissue AGE toxicity in diabetic patients with renal disease.


MHC class II-independent and -dependent T cell expansion and B cell hyperactivity in vivo in mice deficient in CD152 (CTLA-4).
One of the key downregulators of T cell activation is CD152 (CTLA-4). Mice genetically deficient in CD152 (cd152(-/-) mice) develop massive expansion of both CD4(+) and CD8(+) T cells as well as increased numbers of splenic Ig-secreting cells and serum Ig levels. To determine the dependence of the lymphoproliferation and B cell hyperactivity on MHC class II (MHCII), MHCII-deficient (mhcii(-/-)) cd152(-/-) mice were generated. Compared to that in their mhcii(+/+) counterparts, expansion of CD4(+) cells in mhcii(-/-)cd152(-/-) mice was markedly attenuated. Nonetheless, expansion of CD8(+) cells was identical in both sets of mice, demonstrating that the effects of CD152 deficiency on CD4(+) cells can quantitatively be dissociated from those on CD8(+) cells, and pointing to a critical downregulatory role for CD152 in MHCII-independent CD8(+) cell activation in vivo. B cell hyperactivity also developed in mhcii(-/-)cd152(-/-) mice, albeit in a manner less rapid and less intense than that in their mhcii(+/+) counterparts, demonstrating an underlying MHCII-independent diathesis to B cell dysregulation and pointing to a critical downregulatory role for CD152 in MHCII-independent B cell activation in vivo. When human DQ8 was introduced as a transgene into mhcii(-/-)cd152(-/-) mice, B cell hyperactivity was restored to levels observed in mhcii(+/+)cd152(-/-) mice, pointing to a critical downregulatory role for CD152 in MHCII-dependent B cell activation in vivo superimposed upon its downregulatory role on MHCII-independent B cell activation.


Which children are still uninsured and why.
A strong economy and increased enrollment in employer-sponsored health insurance coverage, together with expansions in Medicaid and State Children's Health Insurance Program (SCHIP) led to reductions in uninsurance among low-income American children between 1998 and 2000 (from 15.6% to 13.3%). Nonetheless, 12% (about 9 million) of children remained uninsured. Identifying these children and understanding the factors that contribute to their continued lack of health coverage is key to providing them access to health care. Using 1994, 1998, and 2000 census data, this article analyzes recent trends in children's health coverage, as well as the groups that make up the population of uninsured children. The picture that emerges from these analyses is one of tremendous variation in coverage for different groups of children, with some groups having a higher risk for lacking health insurance. For example, poor children, Hispanics, adolescents, and children with foreign-born parents (particularly those whose parents are not U.S. citizens) are overrepresented among the uninsured. The authors conclude that the strong economy and concomitant increase in employer-based coverage played a bigger part in reducing uninsurance rates than did expansions in public programs. They also argue that lack of participation by eligible children rather than inadequate eligibility levels is the key policy issue, and conclude with several recommendations to increase program participation.


Native Surface Oxides Featured Liquid Metals for Printable Self-Powered Photoelectrochemical Device.
Constructing high-performance photo-electrodes by patterning the photo-active semiconducting components with desirable texture and architecture is one of the most promising approaches to achieve the practical and scale-up application of photo-electric or photoelectrochemical (PEC) devices. However, it is a still big challenge to efficiently and effectively handle nano-structural semiconducting materials into intergraded circuit devices, displaying good electric-contact and stability. Here, a facile manufacture strategy for fabricating native metal-oxides based photo-electrodes by directly printing Ga-based liquid metals is explored. The PEC device, functionalized by the native Ga-oxide functional layer, exhibits self-powered photo-detection behaviors and presents fast photo-electric responsibility in response to the simulated Sunlight illumination. This printable PEC device shows good potential for high sensitive self-powered photo-detector and provides a flexible and versatile approach for the design and fabrication of novel electrode structures.


[Nutraceutical properties of lycopene].
In recent years, dietary recommendations have suggested an increase in the consumption of foods that contain phytochemicals that provide benefits to human health and play an important role in preventing chronic diseases. Lycopene -the carotenoid responsible for the red color of tomatoes- has attracted attention because of its physicochemical and biological properties in the prevention of chronic diseases in which oxidative stress is a major etiological factor, such as cancer, cardiovascular and neurodegenerative diseases, and hypertension, among others. Antioxidants, including lycopene, interact with reactive oxygen species, can mitigate their damaging effects and play a significant role in preventing these diseases. This article presents a review of some epidemiological studies published in recent years on beneficial effects of lycopene in human health.


Nonlinear inversion schemes for fluorescence optical tomography.
Fluorescence optical tomography is a non-invasive imaging modality that employs the absorption and re-emission of light by fluorescent dyes. The aim is to reconstruct the fluorophore distribution in a body from measurements of light intensities at the boundary. Due to the diffusive nature of light propagation in tissue, fluorescence tomography is a nonlinear and severely ill-posed problem, and some sort of regularization is required for a stable solution. In this paper we investigate reconstruction methods based on Tikhonov regularization with nonlinear penalty terms, namely total-variation regularization and a levelset-type method using a nonlinear parameterization of the unknown function. Moreover, we use the full threedimensional nonlinear forward model, which arises from the governing system of partial differential equations. We discuss the numerical realization of the regularization schemes by Newtontype iterations, present some details of the discretization by finite element methods, and outline the efficient implementation of sensitivity systems via adjoint methods. As we will demonstrate in numerical tests, the proposed nonlinear methods provide better reconstructions than standard methods based on linearized forward models and linear penalty terms. We will additionally illustrate, that the careful discretization of the methods derived on the continuous level allows to obtain reliable, mesh independent reconstruction algorithms.


Transfusion-related acute lung injury.
Transfusion-related acute lung injury (TRALI) is a life-threatening adverse effect of transfusion that is occurring at increasing incidence in the United States and that, in the past 2 reporting years, has been the leading cause of transfusion-related death. TRALI and acute lung injury (ALI) share a common clinical definition except that TRALI is temporally and mechanistically related to the transfusion of blood/blood components. In prospective studies, 2 patient groups, 1 requiring cardiac surgery and 1 with hematologic malignancies and undergoing induction chemotherapy, were predisposed. Two different etiologies have been proposed. The first is a single antibody-mediated event involving the transfusion of anti-HLA class I and class II or antigranulocyte antibodies into patients whose leukocytes express the cognate antigens. The second is a 2-event model: the first event is the clinical condition of the patient resulting in pulmonary endothelial activation and neutrophil sequestration, and the second event is the transfusion of a biologic response modifier (including lipids or antibodies) that activates these adherent polymorphonuclear leukocytes (PMNs), resulting in endothelial damage, capillary leak, and TRALI. These hypotheses are discussed, as are the animal models and human studies that provide the experimental and clinical relevance. Prevention, treatment, and a proposed definition of TRALI, especially in the context of ALI, are also examined.


Reasons for Intrauterine Device Use, Discontinuation and Non-Use in Malawi: A Qualitative Study of Women and their Partners.
The copper intrauterine device (IUD) is a safe, long-acting, and effective method of contraception that is under-utilized in many countries, including Malawi. A unique cohort of women who had enrolled in a trial of postpartum IUD use one year earlier gave insights into reasons for using, discontinuing, or not using the IUD. We conducted in-depth interviews with 18 women one year after they participated in a pilot study of a randomized controlled trial of postpartum IUD insertion, and 10 of their male partners. Women and their partners expressed a strong desire for family planning, and perceived numerous benefits of the IUD. However, fear of the IUD was common among successful users and non-users alike. This fear arose from rumours from friends and neighbors who were non-users. How women and their partners responded to this fear affected IUD adoption and continuation. Key themes included (1) Trust in information received from health care providers versus rumours from community members; (2) Partner involvement in IUD decision-making; and (3) Experience with side effects from short-term hormonal contraceptive methods. Broad community education about the IUD's benefits and safety, and proactive counseling to address couples' specific fears, may be needed to increase uptake of the method.


Overexpression and characterization of the human peroxisomal acyl-CoA oxidase in insect cells.
Human liver peroxisomes contain two acyl-CoA oxidases, namely, palmitoyl-CoA oxidase and a branched chain acyl-CoA oxidase. The palmitoyl-CoA oxidase (ACOX) oxidizes the CoA esters of straight chain fatty acids and prostaglandins and donates electrons directly to molecular oxygen, thereby producing H2O2. The inducibility of this H2O2-generating ACOX in rat and mouse liver by peroxisome proliferators and the postulated role of the resulting oxidative stress in hepatocarcinogenesis generated interest in characterizing the structure and function of human ACOX. We have constructed a full-length cDNA encoding a 660-amino acid residue human ACOX and produced a catalytically active human ACOX protein at high levels in Spodoptera frugiperda (Sf9) insect cells using the baculovirus vector. Immunoblot analysis demonstrated that the full-length 72-kDa polypeptide (component A) was partially processed into its constituent 51-kDa (component B) and 21-kDa (component C) products, respectively. Recombinant protein (approximately 20 mg/l x 10(9) cells) was purified to homogeneity by a single-step procedure on a nickel-nitrilo-triacetic acid affinity column. Using the purified enzyme, Km and Vmax values for palmitoyl-CoA were found to be 10 microM and 1.4 units/mg of protein, respectively. The maximal activities for saturated fatty acids were observed with C12-18 substrates. The overexpressed human ACOX protein was identified in the cytoplasm of the insect cells by immunocytochemical staining. Individual expression of either the truncated ACOX 51-kDa (component B) or the 21-kDa (component C) revealed lack of enzyme activity, but co-infection of the insect cells with recombinant viruses expressing components B and C resulted in the formation of an enzymatically active heterodimeric B+C complex which could subsequently be inactivated by dissociating with detergent.


Diffuse pollution of surface water by pharmaceutical products.
Pharmaceutical products for humans or animals, as well as their related metabolites (degradation products) end up in the aquatic environment after use. Recent investigations from abroad show that low concentrations of pharmaceuticals are detectable in municipal waste water, surface water, groundwater and even drinking water. Little is known about the effects, and with that the risk, of long term exposure to low concentrations of pharmaceuticals for aquatic organisms. On the basis of the current knowledge, further attention to map the presence and effects of pharmaceutical residues on aquatic organisms is justified. To map the Dutch situation, recently a monitoring program has started.


Outcome measurement in functional somatic syndromes: SF-36 summary scores and some scales were not valid.
This study aimed to test the validity of the 36-item Short-Form Health Survey (SF-36) scales and summaries in patients with severe functional somatic syndromes (FSS), such as fibromyalgia and irritable bowel syndrome. One hundred twenty patients with severe FSS enrolled in a randomized controlled trial filled in the SF-36 questionnaire. We tested for data quality, central scaling assumptions, and agreement with the conceptual model. Most SF-36 scales were found to be valid; however, three scales (role physical, role emotional, and general health) did not satisfy predefined criteria for construct validity, internal consistency, or targeting to the sample. The correlations between SF-36 scales differed considerably from those reported in the general population. As a consequence, the SF-36 summaries, physical component summary (PCS) and mental component summary (MCS), did not accurately reflect their underlying scales and were negatively correlated (r=-0.46, 95% CI [-0.60 to -0.31]). Although the SF-36 is a valuable instrument to assess perceived health in patients with severe FSS, there are problems with some of the scales and with the scoring procedure of the summaries. The SF-36 PCS may, therefore, not accurately measure the physical health status of these patients. Alternative summary measures are needed.


Eco-genomic analysis of the poleward range expansion of the wasp spider Argiope bruennichi shows rapid adaptation and genomic admixture.
Poleward range expansions are commonly attributed to global change, but could alternatively be driven by rapid evolutionary adaptation. A well-documented example of a range expansion during the past decades is provided by the European wasp spider Argiope bruennichi. Using ecological niche modeling, thermal tolerance experiments and a genome-wide analysis of gene expression divergence, we show that invasive populations have adapted to novel climatic conditions in the course of their expansion. Their climatic niche shift is mirrored in an increased cold tolerance and a population-specific and functionally differentiated gene expression response. We generated an Argiope reference genome sequence and used population genome resequencing to assess genomic changes associated with the new climatic adaptations. We find clear genetic differentiation and a significant admixture with alleles from East Asian populations in the invasive Northern European populations. Population genetic modeling suggests that at least some of these introgressing alleles have contributed to the new adaptations during the expansion. Our results thus confirm the notion that range expansions are not a simple consequence of climate change, but are accompanied by fast genetic changes and adaptations that may be fuelled through admixture between long separated lineages.


Genes induced by growth hormone in a model of adipogenic differentiation.
A substantial number of GH regulated genes have been reported in mature hepatocytes, but genes involved in GH-initiated cell differentiation have not yet been identified. Here we have studied a well-characterised model of GH-dependent differentiation, adipogenesis of 3T3-F442A preadipocytes, to identify genes rapidly induced by GH. Using the suppression subtractive hybridisation technique, we have identified eight genes induced within 60 min of GH treatment, and verified these by northern analysis. Six were identifiable as Stat 2, Stat 3, thrombospondin-1, oncostatin M receptor beta chain, a DEAD box RNA helicase, and muscleblind, a developmental transcription factor. Bioinformatic approaches assigned one of the two remaining unknown genes as a novel 436 residue serine/threonine kinase. As each of the identified genes have important developmental roles, they may be important in initiating GH-induced adipogenesis.


COVID-19 and People Who Use Drugs - A Commentary.
People who use drugs (PWUD) face increased risk of exposure to COVID-19, but also elevated risk associated from injection drug use. We describe factors underlying their increased risk and identify mechanisms for reducing or minimizing rates of COVID-19 transmission and other health outcomes. Our commentary draws upon empirical data, governmental and other reports, and field-based unpublished data from our own studies to inform our conclusion and recommendations. Co-morbid health conditions (eg, diabetes), structural challenges (eg, homelessness, criminal justice involvement), stigma (eg, social devaluation, discrediting), and syndemic clustering of of overdose, HCV, and HIV among PWUD are exacerbated by COVID-19. Beyond the many challenges all people face to remain safe and healthy during the COVID-19 pandemic, PWUD face additional barriers to remaining safe not only from COVID-19 but from negative health outcomes associated with their living environments, socioeconomic positions, and injection drug use. Collaborative efforts among governmental agencies, health providers, SSPs, CBOs, and other agencies providing services to PWUD is essential to the development of programs and services to meet the many needs of PWUD, which have been particularly accentuated during the COVID-19 pandemic.


The role of resilience in rebuilding lives of injured veterans.
The aim of this commentary is to discuss potential clinical implications of introducing resilience-building interventions into care for veterans who are living with a war wound. Some war veterans are expected to live with a wound upon discharge from an active military role and also to fit into civilian life. These lifestyle adjustments can tax the person's coping abilities and in that context may hinder successful adaptation. The experience of living with a wound or wounds, either acute or chronic, is connected to losses, including loss of mobility, loss of financial capacity (unable to work at times) and losses attached to changed social roles. Psychological stress is also a common experience for veterans returning to civilian life. Psychological stress is associated with impaired wound healing. Modern health practice is centred on symptom reduction and working with pathology, however, working with people's adaptive behaviours such as resilience has not been considered. Using the resilience model as a conceptual framework health-care professionals can engage with veterans towards resilience within the context of their personal experience of ill health. Using this contemporary framework for considering these aspects of care has the potential to facilitate resistance to stressors associated with being injured, possibly preventing quality-of-life impairments. There are no declarations of interest.


Intergenerational social mobility and leisure-time physical activity in adulthood: a systematic review.
To systematically review the association between intergenerational social mobility and leisure-time physical activity (LTPA) in adulthood, in order to assess all published evidence relating to the hypothesis that adults socially mobile between childhood and adulthood will have different levels of LTPA than those in the same socioeconomic group across life. A systematic review was carried out following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Studies were identified by searching databases (MEDLINE, Embase, PsycINFO) and reference lists. Eligible studies examined associations between any indicator of social mobility, based on at least one measure of parental socioeconomic position (SEP) and one measure of own adult SEP, and LTPA in adulthood. 13 studies comprising a total of 44 000 participants from the UK, Finland, Sweden, Australia, USA and Brazil were included. Participants were aged 16-70 years and were from population-based surveys, occupational cohorts and primary care registries. Most studies (n=9) used occupational class measures to identify social mobility; education (n=4) and income (n=1) were also used. There was consistent evidence in nine of the 13 studies that stable high socioeconomic groups tended to report the highest levels of participation in LTPA and stable low socioeconomic groups the lowest. Upward and downwardly mobile groups participated in LTPA at levels between these stable groups. Cumulative exposure to higher SEP in childhood and adulthood was associated with higher LTPA in adulthood. Thus, a potential outcome of policies and interventions which aim to minimise exposure to socioeconomic adversity may be increased LTPA among adults. CRD42016036538.


Melanoma risk after ovarian stimulation for in vitro fertilization.
Do women treated with ovarian stimulation for IVF have an increased risk of melanoma? Ovarian stimulation for IVF does not increase risk of melanoma, even after a prolonged follow-up. Although exposure to ultraviolet radiation is the major risk factor for melanoma, associations between female sex steroids and melanoma risk have also been suggested. The results of available studies on fertility drugs and melanoma risk are inconclusive since most studies had several methodological limitations such as short follow-up, a small number of cases and no subfertile comparison group. In 1996, a nationwide historic cohort study (the OMEGA-cohort) was established to examine the risk of cancer after ovarian stimulation for IVF. After a median follow-up of 17 years, cancer incidence was ascertained through linkage with the Netherlands Cancer Registry. Melanoma risk in the cohort was compared with that in the general population and between the IVF group and non-IVF group using multivariable Cox regression analyses. The cohort comprises 19 158 women who received IVF between 1983 and 1995 and a comparison group of 5950 women who underwent subfertility treatments other than IVF. Detailed IVF-treatment data were obtained from the medical records and complete information on parity and age at first birth was obtained through linkage with the Dutch Municipal Personal Records Database. In total, 93 melanoma cases were observed. The risk of melanoma was not elevated among IVF-treated women, neither when compared with the general population (standardized incidence ratio = 0.89; 95% confidence interval (CI): 0.69-1.12), nor when compared with the non-IVF group (adjusted hazard ratio (HR) = 1.27; 95% CI: 0.75-2.15). A higher number of IVF cycles was associated with apparent but statistically non-significant risk increases (5-6 cycles HR = 1.92; ≥7 cycles HR = 1.79). However, no significant trend emerged. In women with more follicle stimulating hormone/human menopausal gonadotrophin ampoules comparable non-significant risk increases were found. A longer follow-up did not increase melanoma risk. Nulliparous women did not have a significantly higher melanoma risk than parous women (HR = 1.22; 95% CI: 0.81-1.84). However, women who were 30 years of age or older at first birth had a significantly higher melanoma risk than women who were younger than 30 years at first birth (age: 30-34 years HR = 4.57; 95% CI: 2.07-10.08, >34 years HR = 2.98; 95% CI: 1.23-7.21). Despite our large cohort, the number of melanoma cases was rather small, especially in our comparison group, which hampered subgroup analyses. Our results are reassuring for women who underwent IVF or are contemplating to start IVF. Since our cohort study is one of the largest published so far, with long-term follow-up, a subfertile comparison group, and detailed IVF-treatment data, our results add important information to the available evidence. This study was supported by grants from the Dutch Cancer Society (NKI 2006-3631), the Health Research and Development Counsel (28-2540) and the Dutch Ministry of Health.


Structure and functional characterization of pyruvate decarboxylase from Gluconacetobacter diazotrophicus.
Bacterial pyruvate decarboxylases (PDC) are rare. Their role in ethanol production and in bacterially mediated ethanologenic processes has, however, ensured a continued and growing interest. PDCs from Zymomonas mobilis (ZmPDC), Zymobacter palmae (ZpPDC) and Sarcina ventriculi (SvPDC) have been characterized and ZmPDC has been produced successfully in a range of heterologous hosts. PDCs from the Acetobacteraceae and their role in metabolism have not been characterized to the same extent. Examples include Gluconobacter oxydans (GoPDC), G. diazotrophicus (GdPDC) and Acetobacter pasteutrianus (ApPDC). All of these organisms are of commercial importance. This study reports the kinetic characterization and the crystal structure of a PDC from Gluconacetobacter diazotrophicus (GdPDC). Enzyme kinetic analysis indicates a high affinity for pyruvate (K M 0.06 mM at pH 5), high catalytic efficiencies (1.3 • 10(6) M(-1) • s(-1) at pH 5), pHopt of 5.5 and Topt at 45°C. The enzyme is not thermostable (T½ of 18 minutes at 60°C) and the calculated number of bonds between monomers and dimers do not give clear indications for the relatively lower thermostability compared to other PDCs. The structure is highly similar to those described for Z. mobilis (ZmPDC) and A. pasteurianus PDC (ApPDC) with a rmsd value of 0.57 Å for Cα when comparing GdPDC to that of ApPDC. Indole-3-pyruvate does not serve as a substrate for the enzyme. Structural differences occur in two loci, involving the regions Thr341 to Thr352 and Asn499 to Asp503. This is the first study of the PDC from G. diazotrophicus (PAL5) and lays the groundwork for future research into its role in this endosymbiont. The crystal structure of GdPDC indicates the enzyme to be evolutionarily closely related to homologues from Z. mobilis and A. pasteurianus and suggests strong selective pressure to keep the enzyme characteristics in a narrow range. The pH optimum together with reduced thermostability likely reflect the host organisms niche and conditions under which these properties have been naturally selected for. The lack of activity on indole-3-pyruvate excludes this decarboxylase as the enzyme responsible for indole acetic acid production in G. diazotrophicus.


Molecular pathways: translational potential of deubiquitinases as drug targets.
The ubiquitin proteasome system (UPS) is the main system for controlled protein degradation and a key regulator of fundamental cellular processes. The dependency of cancer cells on a functioning UPS coupled with the clinical success of bortezomib for the treatment of multiple myeloma have made the UPS an obvious target for drug development. Deubiquitinases (DUB) are components of the UPS that encompass a diverse family of ubiquitin isopeptidases that catalyze the removal of ubiquitin moieties from target proteins or from polyubiquitin chains, resulting in altered signaling or changes in protein stability. Increasing evidence has implicated deregulation of DUB activity in the initiation and progression of cancer. The altered pattern of DUB expression observed in many tumors can potentially serve as a clinical marker for predicting disease outcome and therapy response. The finding of DUB overexpression in tumor cells suggests that they may serve as novel targets for the development of anticancer therapies. Several specific and broad-spectrum DUB inhibitors are shown to have antitumor activity in preclinical in vivo models with low levels of systemic toxicity. Future studies will hopefully establish the clinical potential for DUB inhibitors as a strategy to treat cancer.


Assessing the Impact and Cost of Short-Term Health Workforce in Remote Indigenous Communities in Australia: A Mixed Methods Study Protocol.
Remote Australia is a complex environment characterized by workforce shortages, isolated practice, a large resident Indigenous population, high levels of health need, and limited access to services. In recent years, there has been an increasing trend of utilizing a short-term visiting (fly-in/fly-out) health workforce in many remote areas. However, there is a dearth of evidence relating to the impact of this transitory workforce on the existing resident workforce, consumer satisfaction, and the effectiveness of current services. This study aims to provide rigorous empirical data by addressing the following objectives: (1) to identify the impact of short-term health staff on the workload, professional satisfaction, and retention of resident health teams in remote areas; (2) to identify the impact of short-term health staff on the quality, safety, and continuity of patient care; and (3) to identify the impact of short-term health staff on service cost and effectiveness. Mixed methods will be used. Administrative data will be extracted that relates to all 54 remote clinics managed by the Northern Territory Department of Health, covering a population of 35,800. The study period will be 2010 to 2014. All 18 Aboriginal Community-Controlled Health Services in the Northern Territory will also be invited to participate. We will use these quantitative data to describe staffing stability and turnover in these communities, and then utilize multiple regression analyses to determine associations between the key independent variables of interest (resident staff turnover, stability or median survival, and socioeconomic status, community size, and per capita funding) and dependent variables related to patient care, service cost, quality, and effectiveness. The qualitative component of the study will involve in-depth interviews and focus groups with staff and patients, respectively, in six remote communities. Three communities will be high staff turnover communities and three characterized by low turnover. This will provide information on service quality, impact on resident and visiting staff, and patient satisfaction with the services. The research team will work with staff, patients, and a key stakeholder group of senior policymakers to develop workforce strategies to maintain or attain remote health workforce stability. The study commenced in 2015. As of October 2016, fieldwork has been almost completed and quantitative analysis has commenced. Results are expected to be published in 2017. The study has commenced, but it is too early to provide results or conclusions.


Treatment of lung disease in alpha-1 antitrypsin deficiency: a systematic review.
Alpha-1 antitrypsin deficiency (AATD) is a rare genetic condition predisposing individuals to chronic obstructive pulmonary disease (COPD). The treatment is generally extrapolated from COPD unrelated to AATD; however, most COPD trials exclude AATD patients; thus, this study sought to systematically review AATD-specific literature to assist evidence-based patient management. Standard review methodology was used with meta-analysis and narrative synthesis (PROSPERO-CRD42015019354). Eligible studies were those of any treatment used in severe AATD. Randomized controlled trials (RCTs) were the primary focus; however, case series and uncontrolled studies were eligible. All studies had ≥10 participants receiving treatment or usual care, with baseline and follow-up data (>3 months). Risk of bias was assessed appropriately according to study methodology. In all, 7,296 studies were retrieved from searches; 52 trials with 5,632 participants met the inclusion criteria, of which 26 studies involved alpha-1 antitrypsin augmentation and 17 concerned surgical treatments (largely transplantation). Studies were grouped into four management themes: COPD medical, COPD surgical, AATD specific, and other treatments. Computed tomography (CT) density, forced expiratory volume in 1 s, diffusing capacity of the lungs for carbon monoxide, health status, and exacerbation rates were frequently used as outcomes. Meta-analyses were only possible for RCTs of intravenous augmentation, which slowed progression of emphysema measured by CT density change, 0.79 g/L/year versus placebo (P=0.002), and associated with a small increase in exacerbations 0.29/year (P=0.02). Mortality following lung transplant was comparable between AATD- and non-AATD-related COPD. Surgical reduction of lung volume demonstrated inferior outcomes compared with non-AATD-related emphysema. Intravenous augmentation remains the only disease-specific therapy in AATD and there is evidence that this slows decline in emphysema determined by CT density. There is paucity of data around other treatments in AATD. Treatments for usual COPD may not be as efficacious in AATD, and further studies may be required for this disease group.


Shear deformation-induced anisotropic thermal conductivity of graphene.
Graphene-based materials exhibit intriguing phononic and thermal properties. In this paper, we have investigated the heat conductance in graphene sheets under shear-strain-induced wrinkling deformation, using equilibrium molecular dynamics simulations. A significant orientation dependence of the thermal conductivity of graphene wrinkles (GWs) is observed. The directional dependence of the thermal conductivity of GWs stems from the anisotropy of phonon group velocities as revealed by the G-band broadening of the phonon density of states (DOS), the anisotropy of thermal resistance as evidenced by the G-band peak mismatch of the phonon DOS, and the anisotropy of phonon relaxation times as a direct result of the double-exponential-fitting of the heat current autocorrelation function. By analyzing the relative contributions of different lattice vibrations to the heat flux, we have shown that the contributions of different lattice vibrations to the heat flux of GWs are sensitive to the heat flux direction, which further indicates the orientation-dependent thermal conductivity of GWs. Moreover, we have found that, in the strain range of 0-0.1, the anisotropy ratio of GWs increases monotonously with increasing shear strain. This is induced by the change in the number of wrinkles, which is more influential in the direction perpendicular to the wrinkle texture. The findings elucidated here emphasize the utility of wrinkle engineering for manipulation of nanoscale heat transport, which offers opportunities for the development of thermal channeling devices.


Women's Perceptions and Experiences of Domestic Violence: An Observational Study From Hyderabad, Pakistan.
This community-based observational study of 1,325 women seen for antenatal care examined how women in Pakistan define violence against women (VAW), with an emphasis on domestic violence, what an acceptable response to violence is, reasons for remaining silent, and whether participants are willing to disclose incidents of domestic violence to others. Nearly half of the study participants believed that physical violence was VAW. Verbal abuse, controlling behavior by the husband, conflict with in-laws, overburdening domestic work, and threatening to leave or remarry were also considered VAW. However, only five respondents (0.4%) considered sexual abuse to be VAW. Most women who screened positive for domestic violence responded by remaining silent or verbal fighting back. None sought professional help. Women who decided to remain silent feared that the abuse would escalate or that responding would not help them. Women cited social stigma and concerns about the impact of the violence on children as reasons for not disclosing violent incidents to others or seeking professional help. Women's lack of autonomy further reduced their ability to take steps against violence. Although societal norms, particularly patriarchal beliefs and women's subordination to men, likely explain women's tolerance of abuse, their recognition of physical abuse as violence indicates that they do not necessarily believe it is always justified. Educational interventions to drive changes in the social norms around gender violence along with effective and enforceable legal measures are likely required to ensure women's safety.


Effects of EEDQ on the synthesis and metabolism of dopamine in preweanling and adult rats.
Ontogenetic differences in dopamine (DA) synthesis and metabolism were assessed in 17- and 90-day-old rats injected i.p. with the alkylating agent N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) 24 hr prior to sacrifice. DA synthesis was determined by measuring DOPA accumulation after NSD-1015 induced inhibition of DOPA decarboxylase; whereas, DA turnover was estimated by measuring DA accumulation and DOPAC efflux after pargyline induced inhibition of monoamine oxidase. In addition, some of the rats were pretreated with the competitive D1 and D2 antagonists SCH 23390 (1.0 mg/kg) and sulpiride (100 mg/kg) in order to protect these receptor subtypes from EEDQ-induced inactivation. The latter procedure was used to determine whether EEDQ's presynaptic effects were mediated by D1 and D2 receptors or were nonspecific. The results showed that 7.5 mg/kg EEDQ increased the striatal DA synthesis of both preweanling and adult rats: effects eliminated if D1 and D2 receptors were protected by pretreatment with SCH 23390 and sulpiride. Striatal DA levels of both age groups were depressed by EEDQ treatment, while DA accumulation was unaffected. Age-dependent effects were apparent however, as 7.5 mg/kg EEDQ increased the DOPAC turnover of adult, but not 17-day-old rats. The inability of EEDQ to affect the DOPAC turnover of the younger rats was apparently not dose related, as 15 mg/kg EEDQ did not affect the striatal DOPAC turnover of 17-day-olds. In adult rats, the EEDQ-induced increase in DOPAC turnover was not mediated by DA receptors, as pretreatment with SCH 23390 and sulpiride did not block EEDQ's effects.(ABSTRACT TRUNCATED AT 250 WORDS)


Phenolic Extract from Moringa oleifera Leaves Inhibits Key Enzymes Linked to Erectile Dysfunction and Oxidative Stress in Rats' Penile Tissues.
This study was designed to determine the antioxidant properties and inhibitory effects of extract from Moringa oleifera leaves on angiotensin-I-converting enzyme (ACE) and arginase activities in vitro. The extract was prepared and phenolic (total phenols and flavonoid) contents, radical (nitric oxide (NO), hydroxyl (OH)) scavenging abilities, and Fe(2+)-chelating ability were assessed. Characterization of the phenolic constituents was done via high performance liquid chromatography-diode array detection (HPLC-DAD) analysis. Furthermore, the effects of the extract on Fe(2+)-induced MDA production in rats' penile tissue homogenate as well as its action on ACE and arginase activities were also determined. The extract scavenged NO (∗) , OH (∗) , chelated Fe(2+), and inhibited MDA production in a dose-dependent pattern with IC50 values of 1.36, 0.52, and 0.38 mg/mL and 194.23 µg/mL, respectively. Gallic acid, chlorogenic acid, quercetin, and kaempferol were the most abundant phenolic compounds identified in the leaf extract. The extract also inhibited ACE and arginase activities in a dose-dependent pattern and their IC50 values were 303.03 and 159.59 µg/mL, respectively. The phenolic contents, inhibition of ACE, arginase, and Fe(2+)-induced MDA production, and radical (OH (∗) , NO (∗) ) scavenging and Fe(2+)-chelating abilities could be some of the possible mechanisms by which M. oleifera leaves could be used in the treatment and/or management of erectile dysfunction.


Nutrition surveillance using a small open cohort: experience from Burkina Faso.
Nutritional surveillance remains generally weak and early warning systems are needed in areas with high burden of acute under-nutrition. In order to enhance insight into nutritional surveillance, a community-based sentinel sites approach, known as the Listening Posts (LP) Project, was piloted in Burkina Faso by Action Contre la Faim (ACF). This paper presents ACF's experience with the LP approach and investigates potential selection and observational biases. Six primary sampling units (PSUs) were selected in each livelihood zone using the centric systematic area sampling methodology. In each PSU, 22 children aged between 6 and 24 months were selected by proximity sampling. The prevalence of GAM for each month from January 2011 to December 2013 was estimated using a Bayesian normal-normal conjugate analysis followed by PROBIT estimation. To validate the LP approach in detecting changes over time, the time trends of MUAC from LP and from five cross-sectional surveys were modelled using polynomial regression and compared by using a Wald test. The differences between prevalence estimates from the two data sources were used to assess selection and observational biases. The 95 % credible interval around GAM prevalence estimates using LP approach ranged between +6.5 %/-6.0 % on a prevalence of 36.1 % and +3.5 %/-2.9 % on a prevalence of 10.8 %. LP and cross-sectional surveys time trend models were well correlated (p = 0.6337). Although LP showed a slight but significant trend for GAM to decrease over time at a rate of -0.26 %/visit, the prevalence estimates from the two data sources showed good agreement over a 3-year period. The LP methodology has proved to be valid in following trends of GAM prevalence for a period of 3 years without selection bias. However, a slight observational bias was observed, requiring a periodical reselection of the sentinel sites. This kind of surveillance project is suited to use in areas with high burden of acute under-nutrition where early warning systems are strongly needed. Advocacy is necessary to develop sustainable nutrition surveillance system and to support the use of surveillance data in guiding nutritional programs.


Fibulin-4 is essential for maintaining arterial wall integrity in conduit but not muscular arteries.
Homozygous or compound heterozygous mutations in fibulin-4 (FBLN4) lead to autosomal recessive cutis laxa type 1B (ARCL1B), a multisystem disorder characterized by significant cardiovascular abnormalities, including abnormal elastin assembly, arterial tortuosity, and aortic aneurysms. We sought to determine the consequences of a human disease-causing mutation in FBLN4 (E57K) on the cardiovascular system and vascular elastic fibers in a mouse model of ARCL1B. Fbln4E57K/E57K mice were hypertensive and developed arterial elongation, tortuosity, and ascending aortic aneurysms. Smooth muscle cell organization within the arterial wall of large conducting vessels was abnormal, and elastic fibers were fragmented and had a moth-eaten appearance. In contrast, vessel wall structure and elastic fiber integrity were normal in resistance/muscular arteries (renal, mesenteric, and saphenous). Elastin cross-linking and total elastin content were unchanged in large or small arteries, whereas elastic fiber architecture was abnormal in large vessels. While the E57K mutation did not affect Fbln4 mRNA levels, FBLN4 protein was lower in the ascending aorta of mutant animals compared to wild-type arteries but equivalent in mesenteric arteries. We found a differential role of FBLN4 in elastic fiber assembly, where it functions mainly in large conduit arteries. These results suggest that elastin assembly has different requirements depending on vessel type. Normal levels of elastin cross-links in mutant tissue call into question FBLN4's suggested role in mediating lysyl oxidase-elastin interactions. Future studies investigating tissue-specific elastic fiber assembly may lead to novel therapeutic interventions for ARCL1B and other disorders of elastic fiber assembly.