Eradication of Helicobacter pylori Is Associated with the Progression of Dementia: A Population-Based Study.
Objective. To evaluate the effect of eradication of Helicobacter pylori (H. pylori) on the progression of dementia in Alzheimer's disease (AD) patients with peptic ulcer. Methods. Participants with the diagnosis of AD and peptic ulcer were recruited between 2001 and 2008. We examined the association between eradication of H. pylori and the progression of AD using the multiple regression models. Medication shift from Donepezil, Rivastgmine, and Galantamine to Mematine is defined as progression of dementia according to the insurance of National Health Insurance (NHI) under expert review. Results. Among the 30142 AD patients with peptic ulcers, the ratio of medication shift in AD patients with peptic ulcers is 79.95%. There were significant lower incidence comorbidities (diabetes mellitus, hypertension, cerebrovascular disease, coronary artery disease, congestive heart failure and hyperlipidemia) in patients with H. pylori eradication as compared with no H. pylori eradication. Eradication of H. pylori was associated with a decreased risk of AD progression (odds ratio [OR] 0.35 [0.23-0.52]) as compared with no H. pylori eradication, which was not modified by comorbidities. Conclusions. Eradication of H. pylori was associated with a decreased progression of dementia as compared to no eradication of H. pylori in AD patients with peptic ulcers.


Adipose tissue volume measured by magnetic resonance imaging and computerized tomography in rats.
The primary purpose of this study was to investigate the viability of magnetic resonance imaging (MRI) as a means of measuring the body composition of rodents. To do so we compared adipose tissue (AT) volumes measured by MRI with those obtained by X-ray computerized tomography (CT) in a group of rats (n = 17) varying in weight (465-815 g) and percent body fat (5.4-31.1%), with the latter determined by chemical analysis. For both MRI and CT, AT volumes (cm3) per transverse slice (3-mm thickness, 21-mm centers) were determined using a computer-based image analysis system that permitted detailed comparisons of both visceral and subcutaneous AT depots. Total AT volumes were calculated using a linear interpolation of AT areas obtained on consecutive slices. Correlation coefficients between MRI and CT for visceral [r = 0.98, standard error of estimate (SEE) = 6.8 cm3], subcutaneous (r = 0.98, SEE = 6.5 cm3), and total AT volumes (r = 0.99, SEE = 9.0 cm3) were highly significant (P less than 0.001). Both MRI- and CT-predicted AT mass (assuming fat density = 0.90 g/ml) correlated strongly with chemically extracted lipid (grams) values (r = 0.98, SEE 9.6 g and r = 0.99, SEE = 6.9 g, respectively). Post hoc Scheffé contrasts demonstrated that the mean AT and lipid mass values derived by the three methods were not significantly different (P = 0.01). No systematic differences were observed because the regression lines derived for either MRI or CT vs. chemical analysis were not significantly different from the identity line.(ABSTRACT TRUNCATED AT 250 WORDS)


Synovial fluid pyrophosphate and nucleoside triphosphate pyrophosphatase: comparison between normal and diseased and between inflamed and non-inflamed joints.
Deposition of intra-articular calcium pyrophosphate is associated with both aging and arthropathy; increased concentrations of free pyrophosphate (PPi) may contribute to such deposition. Free pyrophosphate and nucleoside triphosphate pyrophosphatase (NTPase) were estimated in synovial fluids from 50 subjects with normal knees and from 44 patients with rheumatoid arthritis, 61 with pyrophosphate arthropathy, and 59 with osteoarthritis. For arthropathic knees clinically assessed inflammation was classified as active or inactive using a summated score of six clinical features. The order of PPi (mumol/l) and NTPase (mumol PPi/30 min/mg protein) was pyrophosphate arthropathy greater than osteoarthritis greater than rheumatoid arthritis (median PPi, NTPase respectively: for pyrophosphate arthropathy 15.9, 0.45; for osteoarthritis 9.3, 0.25; for rheumatoid arthritis 4.4, 0.18), with significant differences between all groups. In pyrophosphate arthropathy both PPi (mumol/l) and NTPase (mumol PPi/30 min/mg protein) were higher than normal (15.9, 0.45 v 8.6, 0.2 respectively), but findings in osteoarthritis did not differ from normal. The inflammatory state of the knee had a distinct but variable effect on synovial fluid findings in rheumatoid arthritis and pyrophosphate arthropathy, but not in osteoarthritis. There was no correlation of either PPi or NTPase with age, or between PPi and NTPase in any group. This study provides in vivo data for synovial fluid PPi and NTPase. It suggests that factors other than PPi need to be considered in a study of crystal associated arthropathy. Clinical inflammation, as well as diagnosis, is important in synovial fluid studies.


Hispanic ethnicity and vascular access use in patients initiating hemodialysis in the United States.
Hispanics are the largest minority in the United States (comprising 16.3% of the US population) and have 1.5 times the age-, sex-, and race-adjusted incidence of ESRD compared with non-Hispanics. Poor health care access and low-quality care generally received by Hispanics are well documented. However, little is known regarding dialysis preparation of Hispanic patients with progressive CKD. Using data from Medical Evidence Report form CMS-2728-U3, 321,996 adult patients of white or black race were identified who initiated hemodialysis (HD) between July 1, 2005 and December 31, 2008. The form captures Hispanic ethnicity, vascular access use at first outpatient HD, sociodemographic characteristics, and comorbidities. This study also examined whether use of an arteriovenous fistula (AVF) or graft (AVG) was reported. AVF/AVG use was reported in 14.5% of Hispanics and 17.6% in non-Hispanics (P<0.001). The unadjusted prevalence ratio (PR) was 0.85 (95% confidence interval [95% CI], 0.83-0.88), indicating that Hispanics were 15% less likely to use AVG/AVF for their first outpatient HD. Adjustment for age, sex, and race, as well as a large number of comorbidities and frailty indicators, did not change this association (PR, 0.85; 95% CI, 0.83-0.88). Further adjustment for timing of first predialysis nephrology care, however, attenuated the PR by two-thirds (PR, 0.94; 95% CI, 0.92-0.97). Hispanics are less likely to use arteriovenous access for first outpatient HD compared with non-Hispanics, which seems to be explained by variation in the access to predialysis nephrology care.


Strong evidence for ZZ production in pp[over] collisions at sqrt[s]=1.96 TeV.
We report the first evidence of Z boson pair production at a hadron collider with a significance exceeding 4 standard deviations. This result is based on a data sample corresponding to 1.9 fb(-1) of integrated luminosity from pp[over] collisions at sqrt[s]=1.96 TeV collected with the Collider Detector at Fermilab II detector. In the lll'l' channel, we observe three ZZ candidates with an expected background of 0.096(-0.063)+0.092 events. In the llnunu channel, we use a leading-order calculation of the relative ZZ and WW event probabilities to discriminate between signal and background. In the combination of lll'l' and llnunu channels, we observe an excess of events with a probability of 5.1 x 10(-6) to be due to the expected background. This corresponds to a significance of 4.4 standard deviations. The measured cross section is sigma(pp[over]-->ZZ)=1.4(-0.6)+0.7(stat+syst) pb, consistent with the standard model expectation.


Diagnosis and management of hereditary angioedema.
Hereditary angioedema (HAE) is characterized by sudden attacks of deep tissue swelling caused by C1 inhibitor deficiency. Swelling severity can vary from mild to severe, and some patients are at risk for disability and death from either asphyxiation or hypovolemic shock. Many HAE attacks are precipitated by trauma or stress. The extremities, genitalia, trunk, bowels, face, and larynx are commonly affected areas, but swelling can affect any single part of the body or multiple sites. Symptoms typically worsen over 24 to 36 hours and resolve within 48 hours. Because many symptoms of HAE overlap with those of other medical conditions, diagnosis may be delayed. A thorough family history can identify the signature symptoms of HAE, which include a family history of HAE, recurrent edema without urticaria, and symptomatic worsening during puberty. The author presents two hypothetical cases of HAE and reviews the clinical hallmarks of this condition, diagnostic tests, and available treatments.


Gender specific patterns of age-related decline in aortic stiffness: a cardiovascular magnetic resonance study including normal ranges.
Young females exhibit lower cardiovascular event rates that young men, a pattern which is lost, or even reversed with advancing age. As aortic stiffness is a powerful risk factor for cardiovascular events, a gender difference with advancing age could provide a plausible explanation for this pattern. 777 subjects (♀n = 408, ♂n = 369) across a wide range of age (21-85 years) underwent cardiovascular magnetic resonance to assess aortic pulse wave velocity (PWV) and, in addition, aortic distensibility at three levels; 1) ascending aorta (Ao) and 2) proximal descending aorta (PDA) at the level of the pulmonary artery and 3) the abdominal aorta (DDA). There was a strong negative correlation between increasing age and regional aortic distensibility (Ao♀R-0.84, ♂R-0.80, PDA♀R-0.82, ♂R-0.77, DDA♀R-0.80, ♂R-0.71 all p < 0.001) and a strong positive correlation with PWV, (♀R0.53, ♂R 0.63 both p < 0.001). Even after adjustment for mean arterial pressure, body mass index, heart rate, smoking and diabetes, females exhibited a steeper decrease in all distensibility measures in response to increasing age (Ao♀-1.3 vs ♂-1.1 mmHg-1, PDA ♀-1.2 vs ♂-1.0 mmHg, DDA ♀-1.8 vs ♂-1.4 mmHg-1 per 10 years increase in age all p < 0.001). No gender difference in PWV increase with age was observed (p = 0.11). Although advancing age is accompanied by increased aortic stiffness in both males and females, a significant sex difference in the rate of change exists, with females showing a steeper decline in aortic elasticity. As aortic stiffness is strongly related to cardiovascular events our observations may explain the increase in cardiovascular event rates that accompanies the menopausal age in women.


MicroRNA markers for forensic body fluid identification obtained from microarray screening and quantitative RT-PCR confirmation.
MicroRNAs (miRNAs) are non-protein coding molecules with important regulatory functions; many have tissue-specific expression patterns. Their very small size in principle makes them less prone to degradation processes, unlike messenger RNAs (mRNAs), which were previously proposed as molecular tools for forensic body fluid identification. To identify suitable miRNA markers for forensic body fluid identification, we first screened total RNA samples derived from saliva, semen, vaginal secretion, and venous and menstrual blood for the expression of 718 human miRNAs using a microarray platform. All body fluids could be easily distinguished from each other on the basis of complete array-based miRNA expression profiles. Results from quantitative reverse transcription PCR (RT-PCR; TaqMan) assays for microarray candidate markers confirmed strong over-expression in the targeting body fluid of several miRNAs for venous blood and several others for semen. However, no candidate markers from array experiments for other body fluids such as saliva, vaginal secretion, or menstrual blood could be confirmed by RT-PCR. Time-wise degradation of venous blood and semen stains for at least 1 year under lab conditions did not significantly affect the detection sensitivity of the identified miRNA markers. The detection limit of the TaqMan assays tested for selected venous blood and semen miRNA markers required only subpicogram amounts of total RNA per single RT-PCR test, which is considerably less than usually needed for reliable mRNA RT-PCR detection. We therefore propose the application of several stable miRNA markers for the forensic identification of blood stains and several others for semen stain identification, using commercially available TaqMan assays. Additional work remains necessary in search for suitable miRNA markers for other forensically relevant body fluids.


Trail marking by larvae of the cactus moth, Cactoblastis cactorum.
The cactus moth, Cactoblastis cactorum (Berg) (Lepidoptera: Pyralidae), spends most of its larval life feeding within the cladodes of Opuntia cactuses, but the gregarious caterpillars begin their life outside the plant, and in the later instars make intermittent excursions over plant surfaces to access new cladodes and to thermoregulate. The study reported here showed that when the caterpillars move en masse, they mark and follow trails that serve to keep the cohort together. Artificial trails prepared from hexane extracts of the caterpillar's paired mandibular glands were readily followed by the caterpillars. The glands are remarkably large, and their fluid contents, which constitute approximately 1% of the total wet mass of a caterpillar, are secreted onto the substrate as they move. Although the caterpillars also lay down copious quantities of silk, the material in itself neither elicits trail following nor is it a requisite component of pathways that elicit trail following. Previous analyses of the mandibular glands of other species of pyralid caterpillars showed that they contain a series of structurally distinct 2-acyl-1,3 cyclohexane diones. Chemical analysis indicates that the glands of C. cactorum contain structurally similar compounds, and bio- assays indicate that trail following occurs in response to these chemicals. While the mandibular glands' fluids have been shown to act as semiochemicals, effecting both interspecific and intra- specific behavior in other species of pyralids, the present study is the first to report their use as a trail pheromone.


Emergence of Usutu virus in Hungary.
In 2001, Usutu virus (USUV), a mosquito-borne flavivirus of the Japanese encephalitis virus serogroup related to West Nile virus and previously restricted to sub-Saharan Africa, emerged in wild and zoo birds in and around Vienna, Austria. In order to monitor the spread of the infection, a dead bird surveillance program was established in Austria and in neighboring Hungary. In Hungary, 332 dead birds belonging to 52 species were tested for USUV infection between 2003 and 2006. In the first 2 years, all birds investigated were negative. In August 2005, however, USUV was detected in organ samples of a blackbird (Turdus merula), which was found dead in Budapest, Hungary, by reverse transcription-PCR, immunohistochemistry, and in situ hybridization. In July and August 2006, a further six dead blackbirds tested positive for USUV, and the virus was isolated from organ samples of one bird. These birds were also found in urban areas of Budapest. The nearly complete genomic sequence of one Hungarian USUV strain was determined; it was found to share 99.9% identity with the strain that has been circulating in Austria since 2001. This result indicates that the USUV strain responsible for the blackbird die-off in Budapest most likely spread from Austria to Hungary instead of being independently introduced from Africa.


The functional genetic link of NLGN4X knockdown and neurodevelopment in neural stem cells.
Genetic mutations in NLGN4X (neuroligin 4), including point mutations and copy number variants (CNVs), have been associated with susceptibility to autism spectrum disorders (ASDs). However, it is unclear how mutations in NLGN4X result in neurodevelopmental defects. Here, we used neural stem cells (NSCs) as in vitro models to explore the impacts of NLGN4X knockdown on neurodevelopment. Using two shRNAmir-based vectors targeting NLGN4X and one control shRNAmir vector, we modulated NLGN4X expression and differentiated these NSCs into mature neurons. We monitored the neurodevelopmental process at Weeks 0, 0.5, 1, 2, 4 and 6, based on morphological analysis and whole-genome gene expression profiling. At the cellular level, in NSCs with NLGN4X knockdown, we observed increasingly delayed neuronal development and compromised neurite formation, starting from Week 2 through Week 6 post differentiation. At the molecular level, we identified multiple pathways, such as neurogenesis, neuron differentiation and muscle development, which are increasingly disturbed in cells with NLGN4X knockdown. Notably, several postsynaptic genes, including DLG4, NLGN1 and NLGN3, also have decreased expression. Based on in vitro models, NLGN4X knockdown directly impacts neurodevelopmental process during the formation of neurons and their connections. Our functional genomics study highlights the utility of NSCs models in understanding the functional roles of CNVs in affecting neurodevelopment and conferring susceptibility to neurodevelopmental diseases.


Differential inhibition of calcium-dependent and calmodulin-dependent enzymes by drug-calmodulin adducts.
Most of the currently available calmodulin (CaM) antagonists inhibit the actions of CaM by binding directly to it. These CaM-binding drugs tend to be relatively nonselective, because they inhibit the interaction of CaM with most, if not all, of its target enzymes. In order to develop more selective CaM antagonists, we synthesized covalent adducts of CaM and several drugs, including chlorpromazine (CPZ), fluphenazine-N-mustard (FNM), and phenoxybenzamine (PBZ), and examined the effects of these adducts on various CaM and Ca2(+)-dependent enzymes. One of the adducts (CPZ-CaM) selectively inhibited the CaM-induced activation of phosphodiesterase and myosin light chain kinase, without affecting the basal activity of either enzyme. The inhibition of these enzymes by CPZ-CaM was competitive with respect to CaM. CPZ-CaM did not inhibit CaM-sensitive Ca2(+)-ATPase or CaM-dependent protein kinase or the CaM-insensitive enzyme protein kinase C. The FNM-CaM and PBZ-CaM adducts did not inhibit the effects of CaM on any of the enzymes, but they selectively activated two of the enzymes; FNM-CaM slightly activated the CaM-dependent protein kinase, and PBZ-CaM slightly activated phosphodiesterase. These results show that certain covalently linked drug-CaM adducts can differentially inhibit or activate various CaM-sensitive enzymes, and they provide further evidence that it may be possible to develop new classes of CaM antagonists that are directed against the CaM recognition sites on CaM-sensitive enzymes.


Nitrate transceptor(s) in plants.
The availability of mineral nutrients in the soil dramatically fluctuates in both time and space. In order to optimize their nutrition, plants need efficient sensing systems that rapidly signal the local external concentrations of the individual nutrients. Until recently, the most upstream actors of the nutrient signalling pathways, i.e. the sensors/receptors that perceive the extracellular nutrients, were unknown. In Arabidopsis, increasing evidence suggests that, for nitrate, the main nitrogen source for most plant species, a major sensor is the NRT1.1 nitrate transporter, also contributing to nitrate uptake by the roots. Membrane proteins that fulfil a dual nutrient transport/signalling function have been described in yeast and animals, and are called 'transceptors'. This review aims to illustrate the nutrient transceptor concept in plants by presenting the current evidence indicating that NRT1.1 is a representative of this class of protein. The various facets, as well as the mechanisms of nitrate sensing by NRT1.1 are considered, and the possible occurrence of other nitrate transceptors is discussed.


Association of the CTLA-4 gene with rheumatoid arthritis in Chinese Han population.
Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) is important for downregulation of T-cell activation, and CTLA-4 gene polymorphisms have been implicated as risk factors for rheumatoid arthritis (RA). Previous studies of the association between the +49 polymorphism of the CTLA-4 gene in RA have provided conflicting results. In order to determine association of the CTLA-4 gene with RA in Chinese Han population, we used denaturing gradient gel electrophoresis (DGGE) to genotype polymorphisms of four SNPs (MH30, +49, CT60 and JO31) of the CTLA-4 gene in 326 RA patients and 250 healthy controls. Furthermore, meta-analysis of all available studies relating +49 polymorphism to the risk of RA was performed to confirm the disease association. Among the SNPs examined, the genotype frequencies of CTLA-4 +49 and CT60 in RA patients differed significantly from controls (P=0.028 and 0.007). In addition, the distribution of four haplotypes constructed by these two SNPs was significantly different between patients and controls (chi(2)=10.58, d.f. =3, P=0.014). The meta-analysis also revealed that in both European and Asian populations, the CLTA-4 +49 G allele was associated with the risk of RA. These results suggested that the CTLA-4 gene might be involved in the susceptibility to RA in the Chinese Han population and both +49 and CT60 of CTLA-4 gene might be the causal variants in RA disease.


Structural basis of ligand discrimination by two related RNA aptamers resolved by NMR spectroscopy.
In a previous study, an RNA aptamer for the specific recognition of arginine was evolved from a parent sequence that bound citrulline specifically. The two RNAs differ at only 3 positions out of 44. The solution structures of the two aptamers complexed to their cognate amino acids have now been determined by two-dimensional nuclear magnetic resonance spectroscopy. Both aptamers contain two asymmetrical internal loops that are not well ordered in the free RNA but that fold into a compact structure upon ligand binding. Those nucleotides common to both RNAs include a conserved cluster of purine residues, three of which form an uneven plane containing a G:G pair, and two other residues nearly perpendicular to that surface. Two of the three variant nucleotides are stacked on the cluster of purines and form a triple contact to the amino acid side chain, whereas the edge of the third variant nucleotide is capping the binding pocket.


Site-directed mutagenesis and generation of chimeric viruses by homologous recombination in yeast to facilitate analysis of plant-virus interactions.
A yeast homologous recombination system was used to generate mutants and chimeras in the genome of Potato leafroll virus (PLRV). A yeast-bacteria shuttle vector was developed that allows mutants and chimeras generated in yeast to be transformed into Escherichia coli for confirmation of the mutations and transformed into Agrobacterium tumefaciens to facilitate agroinfection of plants by the mutant PLRV genomes. The advantages of the system include the high frequency of recovered mutants generated by yeast homologous recombination, the ability to generate over 20 mutants and chimeras using only two restriction endonuclease sites, the ability to introduce multiple additional sequences using three and four DNA fragments, and the mobilization of the same plasmid from yeast to E. coli, A. tumefaciens, and plants. The wild-type PLRV genome showed no loss of virulence after sequential propagation in yeast, E. coli, and A. tumefaciens. Moreover, many PLRV clones with mutations generated in the capsid protein and readthrough domain of the capsid protein replicated and moved throughout plants. This approach will facilitate the analysis of plant-virus interactions of in vivo-generated mutants for many plant viruses, especially those not transmissible mechanically to plants.


Surrogate decision makers' attitudes towards research decision making for critically ill patients.
To examine the attitudes and preferences of surrogate decision makers (SDMs) regarding their involvement in the consent to research process for ICU patients. We presented 136 SDMs of critically ill patients in five ICUs with four hypothetical research scenarios: baseline interventional study of a placebo controlled RCT; study with higher risk of treatment complication; study comparing two accepted treatments; study with shorter enrolment window. For each we asked SDMs if they would want to be involved in the consent to research decision, and to rate the acceptability of their comfort with, and their sense of burden with their involvement. Participants were screened for symptoms of anxiety and depression using the Hospital Anxiety and Depression Scale. For the baseline scenario, most SDMs wished to be involved in research decision making (90 %; 95 % CI 84-95 %); responses varied little across study permutations. The majority considered their involvement to be acceptable (85 %; 95 % CI 77-90 %), whereas, a small minority rated it as being unacceptable (2 %; 95 % CI 1-6 %). Many were comfortable with being involved (50 %; 95 % CI 41-59 %), but the number decreased when risk of harm was higher (34 %; 95 % CI 26-43 %) or enrolment window was shorter (41 %; 95 % CI 33-50 %). A majority (62 %) reported symptoms of anxiety and many (38 %) had symptoms of depression. Most of the interviewed SDMs wished to be involved in research decision making for critically ill and incapable loved ones. Variability existed, however, in their desire to be involved when decisions were time-sensitive or perceived risk was greater.


Proteomic insight into the pathogenesis of CAPN5-vitreoretinopathy.
CAPN5 Neovascular Inflammatory Vitreoretinopathy (CAPN5-NIV; OMIM 193235) is a poorly-understood rare, progressive inflammatory intraocular disease with limited therapeutic options. To profile disease effector proteins in CAPN5-NIV patient vitreous, liquid vitreous biopsies were collected from two groups: eyes from control subjects (n = 4) with idiopathic macular holes (IMH) and eyes from test subjects (n = 12) with different stages of CAPN5-NIV. Samples were analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Protein expression changes were evaluated by principal component analysis, 1-way ANOVA (significant p-value < 0.05), hierarchical clustering, gene ontology, and pathway representation. There were 216 differentially-expressed proteins (between CAPN5-NIV and control vitreous), including those unique to and abundant in each clinical stage. Gene ontology analysis revealed decreased synaptic signaling proteins in CAPN5-NIV vitreous compared to controls. Pathway analysis revealed that inflammatory mediators of the acute phase response and the complement cascade were highly-represented. The CAPN5-NIV vitreous proteome displayed characteristic enrichment of proteins and pathways previously-associated with non-infectious posterior uveitis, rhegmatogenous retinal detachment (RRD), age-related macular degeneration (AMD), proliferative diabetic retinopathy (PDR), and proliferative vitreoretinopathy (PVR). This study expands our knowledge of affected molecular pathways in CAPN5-NIV using unbiased, shotgun proteomic analysis rather than targeted detection platforms. The high-levels and representation of acute phase response proteins suggests a functional role for the innate immune system in CAPN5-NIV pathogenesis.


Single-junction polymer solar cells with over 10% efficiency by a novel two-dimensional donor-acceptor conjugated copolymer.
Recent advances in bulk heterojunction (BHJ) polymer solar cell (PSC) performance have resulted from compressing the band gap to enhance the short-circuit current density (JSC) while lowering the highest occupied molecular orbital to increase the open-circuit voltage (VOC) and consequently enhance the power conversion efficiencies (PCEs). However, PCEs of PSCs are still constrained by a low JSC, small VOC, and low fill factor (FF). In this study, we report 10.12% PCE from single-junction PSCs based on a novel two-dimensional (2D) conjugated copolymer. By introduction of conjugated 5-alkylthiophene-2-yl side chains to substitute nonconjugated alkoxy side chains in one-dimensional (1D) poly[[4,8-bis[(2-ethylhexyl)oxy]benzo[1,2-b:4,5-b']dithiophene-2,6-diyl][3-fluoro-2-[(2-ethylhexyl)carbonyl]thieno[3,4-b]thiophenediyl]] (PTB7), a novel 2D donor-acceptor low-band-gap conjugated copolymer, poly[[4,8-bis[(5-ethylhexyl)thienyl]benzo[1,2-b;3,3-b]dithiophene-2,6-diyl][3-fluoro-2-[(2-ethylhexyl)carbonyl]thieno[3,4-b]thiophenediyl]] (PTB7-DT), is developed. 2D PTB7-DT is further systematically investigated by absorption spectroscopy, cyclic voltammetry, charge carrier mobility measurement, thin film morphology, and wide-angle X-ray diffraction and compared with 1D PTB7. In comparison with 1D PTB7, 2D PTB7-DT possesses a narrower band gap, tighter π-π stacking, and higher charge carrier mobility. These results are consistent with the observation from first-principle calculations. Consequently, the single-junction PSCs based on 2D PTB7-DT exhibit a PCE of 10.12% with a high JSC, larger VOC, and high FF in comparison with the PSCs based on 1D PTB7.


Transient receptor potential channel modulators as pharmacological treatments for lower urinary tract symptoms (LUTS): myth or reality?
Transient receptor potential (TRP) channels belong to the most intensely pursued drug targets of the last decade. These ion channels are considered promising targets for the treatment of pain, hypersensitivity disorders and lower urinary tract symptoms (LUTS). The aim of the present review is to discuss to what extent TRP channels have adhered to their promise as new pharmacological targets in the lower urinary tract (LUT) and to outline the challenges that lie ahead. TRP vanilloid 1 (TRPV1) agonists have proven their efficacy in the treatment of neurogenic detrusor overactivity (DO), albeit at the expense of prolonged adverse effects as pelvic 'burning' pain, sensory urgency and haematuria. TRPV1 antagonists have been very successful in preclinical studies to treat pain and DO. However, clinical trials with the first generation TRPV1 antagonists were terminated early due to hyperthermia, a serious, on-target, side-effect. TRP vanilloid 4 (TRPV4), TRP ankyrin 1 (TRPA1) and TRP melastatin 8 (TRPM8) have important sensory functions in the LUT. Antagonists of these channels have shown their potential in pre-clinical studies of LUT dysfunction and are awaiting clinical validation.


Evaluation of teeth injuries in Beagle dogs caused by autoclaved beef bones used as a chewing item to remove dental calculus.
Dental calculus (DC) is the most widespread oral problem in domestic dogs. Chewing items are used to remove DC from the tooth surface; they also favor oral health and animal welfare. Raw beef bone mastication also shortly reduces DC in adult dogs. However, it can cause oral lesions and hence is not popular. This study evaluated the impact of bone mastication on the dental roots, enamel, and gingiva of dogs. Twelve adult Beagle dogs were randomly divided into 2 treatment groups in a completely randomized block design: cortical bone (CB) or spongy bone (SB). Intraoral radiographs were obtained on days 0 and 14, and calculus assessment was performed using images captured on days 0, 3, 6, 9, 12, and 14; an integration program was used to measure the proportion between the area covered by calculus and the total area of teeth. DC was completely removed from the first and second premolars and molars from both the arcades in less than 3 days of supplementation, indicating that these teeth were frequently used for chewing (P < 0.10). Bones were highly effective for DC removal and gingival inflammation reduction. Despite the hardness of bones, no lesions or teeth root and enamel fracture, or esophageal or intestinal obstructions-complications related to bone ingestion-were noted. However, SB showed some gingival lesions (n = 4) and bone remnants between teeth (n = 2). Gingival lesions were caused by the daily and continuous supply of new pieces of bone for 13 days. Specific pieces of bone should be used for oral home care programs because they shortly remove almost 90% of DC, allowing longer intervals between periodontal cleaning procedures. Long-term studies are required to evaluate the use of bones and evaluate their impact on teeth and periodontium after prolonged supplementation.


Dye-sensitized nickel(II)oxide photocathodes for tandem solar cell applications.
To date, nickel(II) oxide (NiO) is one of the few p-type semiconductors that has successfully been used for the construction of dye-sensitized photocathodes as well as tandem dye-sensitized solar cells. In this study we present a novel fabrication method for the preparation of mesoporous NiO films based on preformed NiO nanopowders. Critical properties such as pore-size distribution, crystallinity, and internal surface area of the resulting NiO films were controlled through the sintering process and optimized for their application as dye-sensitized photocathodes, resulting in a significantly increased photovoltaic performance, compared to earlier studies. A series of different sensitizers and electrolytes was scrutinized for their application in dye-sensitized NiO photocathodes. Despite its limited absorption range the dye coumarin 343 clearly outperforms other sensitizers used in this study. Values for short-circuit current densities of 2.13 mA cm(-2) and overall energy conversion efficiencies of 0.033% under simulated sunlight (AM1.5, 1000 W m(-2)) are the highest values reported in literature so far.


Carbon allocation in ectomycorrhizas: identification and expression analysis of an Amanita muscaria monosaccharide transporter.
Ectomycorrhizas are formed between certain soil fungi and fine roots of predominantly woody plants. An important feature of this symbiosis is the supply of plant-derived carbohydrates to the fungus. As a first step toward a better understanding of the molecular basis of this process, we cloned a monosaccharide transporter from the ectomycorrhizal fungus Amanita muscaria. Degenerate oligonucleotide primers were designed to match conserved regions from known fungal sugar transporters. A cDNA fragment of the transporter was obtained from mycorrhizal mRNA by reverse transcription-polymerase chain reaction. This fragment was used to identify a clone (AmMst1) encoding the entire monosaccharide transporter in a Picea abies/A. muscaria mycorrhizal cDNA library. The cDNA codes for an open reading frame of 520 amino acids, showing best homology to a Neurospora crassa monosaccharide transporter. The function of AmMST1 as monosaccharide transporter was confirmed by heterologous expression of the cDNA in a Schizosaccharomyces pombe mutant lacking a monosaccharide uptake system. AmMst1 was constitutively expressed in fungal hyphae under all growth conditions. Nevertheless, in mycorrhizas as well as in hyphae grown at monosaccharide concentrations above 5 mM, the amount of AmMst1 transcript increased fourfold. We therefore suggest that AmMst1 is upregulated in ectomycorrhizas by a monosaccharide-controlled mechanism.


Factors Predicting Bereaved Caregiver Perception of Quality of Care in the Final Week of Life: Implications for Health Care Providers.
Cancer caregivers are key stakeholders in the final weeks of life and in bereavement. Research has highlighted end-of-life (EOL) factors important to caregivers, as well as factors contributing to caregiver mental health and bereavement outcomes. There has been limited data on factors predicting caregiver perceptions of quality of EOL care. This study's purpose was to identify modifiable predictors of caregivers' Caregiver Evaluation of Quality of End of Life Care (CEQUEL) scores, with the broader aim of informing clinical interventions to improve caregiver impressions of care and subsequent bereavement adjustment. Study data came from Coping with Cancer I (CwC1). CwC1 investigators interviewed advanced cancer patients and caregivers prior to the patient's death (Wave 1) and reinterviewed caregivers following the death (Wave 2) (N=275 dyads). The authors identified potential Wave 1 predictors of CEQUEL scores and performed a series of linear regression analyses to identify a parsimonious predictive model using corrected Akaike's Information Criterion (AICc) values. In adjusted analyses, caregivers rated quality of care as poorer when patients died in a hospital (B=-1.40, SE=0.40, p=0.001) (B, unstandardized regression coefficient; SE, standard error) or had less than one week of inpatient hospice care (B=-1.98, SE=-0.70, p=0.006). Whole-person physician care and caregiver religiosity were associated with perceived higher quality of care in unadjusted, but not adjusted, analyses. Findings suggest that place of death and hospice length of stay best predict bereaved caregiver evaluations of quality of EOL care. These findings equip health care providers with modifiable targets to improve caregivers' experience of EOL care and subsequent bereavement.


Problem Gambling Associated With Aripiprazole in First-Episode Psychosis Patients: A Series of 6 Case Reports.
Aripiprazole (ARI), an antipsychotic drug used to treat various mental health disorders, has recently been associated with the emergence of problem gambling (PBG). However, few cases have been reported in the schizophrenia-related psychotic disorders population, and even fewer provided sufficient details to systematically assess the causality of the association. This article describes 6 cases with first-episode psychosis in whom PBG emerged while on ARI. Detailed information was gathered from clinical staff and patients' families to systematically assess the causal link between ARI and the emergence of PBG using the Naranjo and Liverpool Adverse Drug Reaction scales. Five of these cases were previously diagnosed with a substance use disorder and/or cluster B personality traits. Five had received a more potent dopaminergic antagonist treatment before being switched to ARI. Two of them had presented PBG before being diagnosed with a psychotic disorder. The level of certainty about the causal role of ARI varied from possible to certain, and in 4 cases, the 2 scales yielded different ratings. Although these cases suggest that ARI may be associated with the emergence of PBG in the early course of schizophrenia-related psychotic disorders, they cannot prove the causality or the strength of this association. They provide the impetus to perform adequately powered and well-controlled prospective studies to draw more definite conclusion about the causality of this association and, in the meantime, further emphasize the need to carefully assess PBG in this population.


Endocarditis-related cerebral aneurysms: radiologic changes with treatment.
To document the response of mycotic aneurysms to antibiotic therapy and correlate these findings with patient outcome. Clinical findings, CT studies, and serial cerebral angiograms of patients with endocarditis related aneurysms seen over 10 years were retrospectively reviewed. In 14 patients infective endocarditis was diagnosed. The patients presented with subarachnoid haemorrhage (4 patients), stroke (9 patients), and seizure (1 patient). CT findings were intracerebral hematoma (5 patients), infarcts (4 patients), subarachnoid hemorrhage (4 patients), and aneurysms (2 patients). On angiography, 10 (71%) patients had single aneurysms, and 4 (29%) patients had multiple aneurysms. Eighteen aneurysms were detected, of which 6 (33%) were centrally located, and 12 (66%) were located peripherally. The most common site was the peripheral middle cerebral artery (56%). Serial angiography during antibiotic treatment demonstrated complete resolution of 6 aneurysms (33%), with 12 aneurysms remaining after 6 weeks of treatment. Of the latter, there was no change in size in 6 aneurysms (33%), a decrease in size in 3 aneurysms (17%) and an increase in size in 3 aneurysms (17%). No new aneurysms appeared. Surgery was performed on 10 patients with residual aneurysms, 11 aneurysms being excised or clipped. After 6 weeks' treatment, there was complete recovery in 7 (50%) patients, permanent neurologic deficits in 6 patients, and death from aneurysm rebleed in 1 patient. Follow-up angiography is recommended in all patients with mycotic aneurysms to assess response to antibiotic therapy, to detect new aneurysms, and to identify those aneurysms with no response or with enlargement.


Hepatocellular Shuttling and Recirculation of Sorafenib-Glucuronide Is Dependent on Abcc2, Abcc3, and Oatp1a/1b.
Recently, an efficient liver detoxification process dubbed "hepatocyte hopping" was proposed on the basis of findings with the endogenous compound, bilirubin glucuronide. According to this model, hepatocytic bilirubin glucuronide can follow a liver-to-blood shuttling loop via Abcc3 transporter-mediated efflux and subsequent Oatp1a/1b-mediated liver uptake. We hypothesized that glucuronide conjugates of xenobiotics, such as the anticancer drug sorafenib, can also undergo hepatocyte hopping. Using transporter-deficient mouse models, we show here that sorafenib-glucuronide can be extruded from hepatocytes into the bile by Abcc2 or back into the systemic circulation by Abcc3, and that it can be taken up efficiently again into neighboring hepatocytes by Oatp1a/1b. We further demonstrate that sorafenib-glucuronide excreted into the gut lumen can be cleaved by microbial enzymes to sorafenib, which is then reabsorbed, supporting its persistence in the systemic circulation. Our results suggest broad relevance of a hepatocyte shuttling process known as "hepatocyte hopping"-a novel concept in clinical pharmacology-for detoxification of targeted cancer drugs that undergo hepatic glucuronidation, such as sorafenib.


Immediate versus delayed IUD insertion after uterine aspiration.
Intrauterine devices (IUDs) provide highly effective, reversible, long-term contraception that is appropriate for many women after first-trimester uterine aspiration. However, the effects of immediate versus delayed IUD insertion after uterine aspiration on rates of complications and IUD use are uncertain. We performed a randomized noninferiority trial involving women undergoing uterine aspiration for induced or spontaneous abortion at 5 to 12 weeks of gestation who desired an IUD. Subjects were randomly assigned (in a 5:6 ratio) to IUD insertion immediately after the procedure or 2 to 6 weeks afterward (delayed insertion). The primary outcome was the rate of IUD expulsion 6 months after IUD insertion; an expulsion rate 8 percentage points higher in the immediate-insertion group was defined as inferior. Among 575 women who underwent randomization, an IUD was inserted in 100% (258 of 258) of the women in the immediate-insertion group and in 71.3% (226 of 317) of those in the delayed-insertion group (difference, 28.7 percentage points; 95% confidence interval [CI], 23.7 to 33.7). The 6-month expulsion risk was 5.0% (13 of 258 women) after immediate insertion and 2.7% (6 of 226) after delayed insertion (difference, 2.3 percentage points; 95% CI, -1.0 to 5.8), which was consistent with the predefined criterion for noninferiority. Six-month rates of IUD use were higher in the immediate-insertion group (92.3%, vs. 76.6% after delayed insertion; P<0.001). Adverse events were rare and did not differ significantly between groups. No pregnancies occurred in the immediate-insertion group; five occurred in the delayed-insertion group (P=0.07), all in women who never received an IUD. The 6-month rate of expulsion of an IUD after immediate insertion was higher than but not inferior to that after delayed insertion. Immediate insertion resulted in higher rates of IUD use at 6 months, without an increased risk of complications. (Funded by the Susan Thompson Buffett Foundation; ClinicalTrials.gov number, NCT00562276.).


Investigating generalizability of results from a randomized controlled trial of the management of chronic widespread pain: the MUSICIAN study.
The generalisability of randomised controlled trials will be compromised if markers of treatment outcome also affect trial recruitment. In a large trial of chronic widespread pain, we aimed to determine the extent to which randomised participants represented eligible patients, and whether factors predicting randomisation also influenced trial outcome. Adults from 8 UK general practices were surveyed to determine eligibility for a trial of 2 interventions (exercise and cognitive behavioural therapy [CBT]). Amongst those eligible, logistic regression identified factors associated with reaching the randomisation step in the recruitment process. The main trial analysis was recomputed, weighting for the inverse of the likelihood of reaching the randomisation stage, and the numbers needed to treat were calculated for each treatment. Eight hundred eighty-four persons were identified as eligible for the trial, of whom 442 (50%) were randomised. Several factors were associated with the likelihood of reaching the randomisation stage: higher body mass index (odds ratio: 1.99; 0.85-4.61); more severe/disabling pain (1.90; 1.21-2.97); having a treatment preference (2.11; 1.48-3.00); and expressing positivity about interventions offered (exercise: 2.66; 1.95-3.62; CBT: 3.20; 2.15-4.76). Adjusting for this selection bias decreased the treatment effect associated with exercise and CBT but increased that observed for combined therapy. All were associated with changes in numbers needed to treat. This has important implications for the design and interpretation of pain trials generally.


Analysis of nisin A and some of its variants using Fourier transform ion cyclotron resonance mass spectrometry.
The lantibiotic nisin and some of its variants and degradation products have been characterized, using a 9.4-T Fourier transform ion cyclotron resonance mass spectrometer and electrospray ionization. The abundances of all products in the sample (i.e., major component, variants, degradation products, and adducts) have been measured quantitatively. The mass resolution obtained in the electrospray ionisation mass spectra was approximately 100,000 over the measured range. The resulting mass accuracy, better than 0.7 ppm (or within 0.001 Da) allowed the molecular masses and in many cases chemical formulae of most components in the mixture to be identified unambiguously. Additionally, amino acid sequence information on nisin and a variant [nisin + 18 Da] was obtained using sustained off-resonance irradiation collisional activated decomposition (SORI-CAD) of mass-selected precursor ions. Even after introducing collision gas into the mass analyser for the SORI-CAD experiments, the mass accuracy in the fragment ion mass spectra was approximately 5 ppm. It was established that the [nisin + 18 Da] molecule, present as a minor component in the mixture, was a species formed predominantly via hydration of nisin at position 33, i.e., [Ser33]nisin, with a small contribution due to hydration at position 5,[2-hydroxy-Ala5]nisin.


Orbital shaker technology for the cultivation of mammalian cells in suspension.
For large-scale applications in biotechnology, cultivation of mammalian cells in suspension is an essential prerequisite. Typically, suspension cultures are grown in glass spinner flasks filled to less than 50% of the nominal volume. We propose a superior system for suspension cultures of mammalian cells based on orbital shaker technology. We found that "square-shaped" bottles (square bottles) provide an inexpensive but efficient means to grow HEK-293 EBNA and CHO-DG44 cells to high density. Cultures in agitated 1-L square bottles exceeded the performance of cultures in spinner flasks, reaching densities up to 7 x 10(6) cells/mL for HEK-293 EBNA cells and 5 x 10(6) cells/mL for CHO-DG44 cells in comparison to (2.5-4) x 10(6) cells/mL for cultures of the same cells grown in spinner flasks. For 1-L square bottles, optimal cell growth and viability were observed with a filling volume of 30-40% of the nominal volume and an agitation speed of 130 rpm at a rotational diameter of 2.5 cm. Transient reporter gene expression following gene delivery by calcium phosphate-DNA co-precipitation was the same or slightly better for HEK-293 EBNA cells grown in square bottles as compared to spinner flasks. Reductions in cost, simplified handling, and better performance in cell growth and viability make the agitated square bottle a new and very promising tool for the cultivation of mammalian cells in suspension.


Compression therapy promotes proliferative repair during rat Achilles tendon immobilization.
Achilles tendon ruptures are treated with an initial period of immobilization, which obstructs the healing process partly by a reduction of blood circulation. Intermittent pneumatic compression (IPC) has been proposed to enhance tendon repair by stimulation of blood flow. We hypothesized that daily IPC treatment can counteract the deficits caused by 2 weeks of immobilization post tendon rupture. Forty-eight Sprague-Dawley SD) rats, all subjected to blunt Achilles tendon transection, were divided in three equal groups. Group A was allowed free cage activity, whereas groups B-C were immobilized at the operated hindleg. Group C received daily IPC treatment. Two weeks postrupture the rats were euthanatized and the tendons analyzed with tensile testing and histological assessments of collagen organization and collagen III-LI occurrence. Immobilization significantly reduced maximum force, energy uptake, stiffness, tendon length, transverse area, stress, organized collagen diameter and collagen III-LI occurrence by respectively 80, 75, 77, 22, 47, 65, 49, and 83% compared to free mobilization. IPC treatment improved maximum force 65%, energy 168%, organized collagen diameter 50%, tendon length 25%, and collagen III-LI occurrence 150% compared to immobilization only. The results confirm that immobilization impairs healing after tendon rupture and furthermore demonstrate that IPC-treatment can enhance proliferative tendon repair by counteracting biomechanical and morphological deficits caused by immobilization.


Molecular recognition in a lattice model: an enumeration study.
We investigate the mechanisms underlying selective molecular recognition of single heteropolymers at chemically structured planar surfaces. To this end, we study systems with two-letter (HP) lattice heteropolymers by exact enumeration techniques. Selectivity for a particular surface is defined by an adsorption energy criterion. We analyze the distributions of selective sequences and the role of mutations. A particularly important factor for molecular recognition is the small-scale structure on the polymers.


Rapid genomic characterization of the genus vitis.
Next-generation sequencing technologies promise to dramatically accelerate the use of genetic information for crop improvement by facilitating the genetic mapping of agriculturally important phenotypes. The first step in optimizing the design of genetic mapping studies involves large-scale polymorphism discovery and a subsequent genome-wide assessment of the population structure and pattern of linkage disequilibrium (LD) in the species of interest. In the present study, we provide such an assessment for the grapevine (genus Vitis), the world's most economically important fruit crop. Reduced representation libraries (RRLs) from 17 grape DNA samples (10 cultivated V. vinifera and 7 wild Vitis species) were sequenced with sequencing-by-synthesis technology. We developed heuristic approaches for SNP calling, identified hundreds of thousands of SNPs and validated a subset of these SNPs on a 9K genotyping array. We demonstrate that the 9K SNP array provides sufficient resolution to distinguish among V. vinifera cultivars, between V. vinifera and wild Vitis species, and even among diverse wild Vitis species. We show that there is substantial sharing of polymorphism between V. vinifera and wild Vitis species and find that genetic relationships among V. vinifera cultivars agree well with their proposed geographic origins using principal components analysis (PCA). Levels of LD in the domesticated grapevine are low even at short ranges, but LD persists above background levels to 3 kb. While genotyping arrays are useful for assessing population structure and the decay of LD across large numbers of samples, we suggest that whole-genome sequencing will become the genotyping method of choice for genome-wide genetic mapping studies in high-diversity plant species. This study demonstrates that we can move quickly towards genome-wide studies of crop species using next-generation sequencing. Our study sets the stage for future work in other high diversity crop species, and provides a significant enhancement to current genetic resources available to the grapevine genetic community.


Increased mitochondrial uncoupling proteins, respiratory uncoupling and decreased efficiency in the chronically infarcted rat heart.
Heart failure patients have abnormal cardiac high energy phosphate metabolism, the explanation for which is unknown. Patients with heart failure also have elevated plasma free fatty acid (FFA) concentrations. Elevated FFA levels are associated with increased cardiac mitochondrial uncoupling proteins (UCPs), which, in turn, are associated with decreased mitochondrial respiratory coupling and low cardiac efficiency. Here, we determined whether increased mitochondrial UCP levels contribute to decreased energetics in the failing heart by measuring UCPs and respiration in mitochondria isolated from the viable myocardium of chronically infarcted rat hearts and measuring efficiency (hydraulic work/O(2) consumption) in the isolated, working rat heart. Ten weeks after infarction, cardiac levels of UCP3 were increased by 53% in infarcted, failing hearts that had ejection fractions less than 45%. Cardiac UCP3 levels correlated positively with non-fasting plasma FFAs (r=0.81; p<0.01). Mitochondria from failing hearts were less coupled than those from control hearts, as demonstrated by the lower ADP/O ratio of 1.9+/-0.1 compared with 2.5+/-0.2 in controls (p<0.05). The decreased ADP/O ratio was reflected in an efficiency of 14+/-2% in the failing hearts when perfused with 1 mM palmitate, compared with 20+/-1% in controls (p<0.05). We conclude that failing hearts have increased UCP3 levels that are associated with high circulating FFA concentrations, mitochondrial uncoupling, and decreased cardiac efficiency. Thus, respiratory uncoupling may underlie the abnormal energetics and low efficiency in the failing heart, although whether this is maladaptive or adaptive would require direct investigation.


Genotype diversity and molecular evolution of noroviruses: A 30-year (1982-2011) comprehensive study with children from Northern Brazil.
A chronologically comprehensive 30-year study was conducted that involved children living in Belém, in the Amazon region of Northern Brazil, who participated in eight different studies from October 1982 to April 2011. The children were followed either in the community or in health units and hospitals in order to identify the norovirus genotypes involved in infections during this time. A total of 2,520 fecal specimens were obtained and subjected to RT-PCR and nucleotide sequencing for regions A, B, C, D and P2 of the viral genome. An overall positivity of 16.9% (n = 426) was observed, and 49% of the positive samples were genotyped (208/426), evidencing the presence of several genotypes as follows: Polymerase gene (GI.P4, GII.Pa, GII.Pc, GII.Pe, GII.Pg, GII.Pj, GII.P3, GII.P4, GII.P6, GII.P7, GII.P8, GII.P12, GII.P13, GII.P14, GII.P21, GII.P22), and VP1 gene (GI.3, GI.7, GII.1, GII.2, GII.3, GII.4, GII.6, GII.7, GII.8, GII.10, GII.12, GII.14, GII.17, GII.23). The GII.P4/GII.4 genotype determined by both open reading frames (ORFs) (partial polymerase and VP1 genes) was found for 83 samples, and analyses of the subdomain P2 region showed 10 different variants: CHDC (1970s), Tokyo (1980s), Bristol_1993, US_95/96, Kaiso_2003, Asia_2003, Hunter_2004, Yerseke_2006a, Den Haag_2006b (subcluster "O") and New Orleans_2009. Recombination events were confirmed in 47.6% (n = 20) of the 42 samples with divergent genotyping by ORF1 and ORF2 and with probable different breakpoints within the viral genome. The evolutionary analyses estimated a rate of evolution of 1.02 x 10-2 and 9.05 x 10-3 subs./site/year using regions C and D from the VP1 gene, respectively. The present research shows the broad genetic diversity of the norovirus that infected children for 30 years in Belém. These findings contribute to our understanding of noroviruses molecular epidemiology and viral evolution and provide a baseline for vaccine design.


The immune landscape in BCR-ABL negative myeloproliferative neoplasms: inflammation, infections and opportunities for immunotherapy.
Breakpoint cluster region-Abelson (BCR-ABL) negative myeloproliferative neoplasms (MPNs) are chronic myeloid neoplasms initiated by the acquisition of gene mutation(s) in a haematopoietic stem cell, leading to clonal expansion and over-production of blood cells and their progenitors. MPNs encompass a spectrum of disorders with overlapping but distinct molecular, laboratory and clinical features. This includes polycythaemia vera, essential thrombocythaemia and myelofibrosis. Dysregulation of the immune system is key to the pathology of MPNs, supporting clonal evolution, mediating symptoms and resulting in varying degrees of immunocompromise. Targeting immune dysfunction is an important treatment strategy. In the present review, we focus on the immune landscape in patients with MPNs - the role of inflammation in disease pathogenesis, susceptibility to infection and emerging strategies for therapeutic immune modulation. Further detailed work is required to delineate immune perturbation more precisely in MPNs to determine how and why vulnerability to infection differs between clinical subtypes and to better understand how inflammation results in a competitive advantage for the MPN clone. These studies may help shed light on new designs for disease-modifying therapies.


Hemosiderin deposition in the brain as footprint of high-altitude cerebral edema.
Based on recent findings of microhemorrhages (MHs) in the corpus callosum (CC) in 3 individuals after nonfatal high-altitude cerebral edema (HACE), we hypothesized that hemosiderin depositions in the brain after high-altitude exposure are specific for HACE and remain detectable over many years. This was a cross-sectional study involving 37 mountaineers in 4 groups: 10 had experienced HACE, 8 high-altitude pulmonary edema, 11 severe acute mountain sickness, and 8 had climbed to altitudes ≥6,962 m without developing any high-altitude illness. HACE was defined as ataxia necessitating assistance with walking and/or decreased consciousness. Within <1 to 38 months after the qualifying incident, MRI of the brain was performed using a 3-tesla scanner and high-resolution susceptibility-weighted magnetic resonance sequences for detection of hemosiderin depositions, which were quantified by a score. Unequivocal MHs located in the splenium of the CC were found in 8 subjects and questionable MHs were found in 2 subjects 1 to 35 months after HACE. They were located outside the CC in 5 more severe cases. MHs remained unchanged in those reexamined after 12 to 50 months. A few unequivocal MHs in the splenium of the CC were found in one subject after severe acute mountain sickness, while one subject with high-altitude pulmonary edema and 2 of the extreme altitude climbers had questionable lesions. In all other subjects, MHs were unequivocally absent. MHs detectable by susceptibility-weighted MRI predominantly in the splenium of the CC are long-lasting footprints of HACE.


Hyaluronic acid and beta cyclodextrins films for the release of corneal epithelial cells and dexamethasone.
In this work we prepared hydrogels based on hyaluronic acid and β-cyclodextrins to sustain the release of both corneal epithelial cells and dexamethasone. This steroid is administered as eye drops several times per day to reduce the risk of rejection in the post operative period after the cornea transplantation and cell release techniques. Hydrogels were produced by crosslinking an amino derivative of hyaluronic acid, with the divinyl sulfone derivative of β-cyclodextrins, this last employed as a crosslinker and solubilizing agent. Drug release studies revealed that dexamethasone containing samples are able to extend the release of this drug for at least five days. Biological studies, conducted with human corneal epithelial cells, showed that it is possible to employ the hydrogels for the temporary seeding of the cells and their potential release onto the cornea.


Diagnosis of pulmonary tuberculosis in HIV-positive patients by microscopic observation drug susceptibility assay.
The microscopic observation drug susceptibility assay (MODS) is a novel and promising test for the early diagnosis of tuberculosis (TB). We evaluated the MODS assay for the early diagnosis of TB in HIV-positive patients presenting to Pham Ngoc Thach Hospital for Tuberculosis and Lung Diseases in southern Vietnam. A total of 738 consecutive sputum samples collected from 307 HIV-positive individuals suspected of TB were tested by smear, MODS, and the mycobacteria growth indicator tube method (MGIT). The diagnostic sensitivity and specificity of MODS compared to the microbiological gold standard (either smear or MGIT) were 87 and 93%, respectively. The sensitivities of smear, MODS, and MGIT were 57, 71, and 75%, respectively, against clinical gold standard (MODS versus smear, P<0.001; MODS versus MGIT, P=0.03). The clinical gold standard was defined as patients who had a clinical examination and treatment consistent with TB, with or without microbiological confirmation. For the diagnosis of smear-negative patients, the sensitivities of MODS and MGIT were 38 and 45%, respectively (P=0.08). The median times to detection using MODS and MGIT were 8 and 11 days, respectively, and they were 11 and 17 days, respectively, for smear-negative samples. The original bacterial/fungal contamination rate of MODS was 1.1%, while it was 2.6% for MGIT. The cross-contamination rate of MODS was 4.7%. In conclusion, MODS is a sensitive, specific, and rapid test that is appropriate for the detection of HIV-associated TB; its cost and ease of use make it particularly useful in resource-limited settings.


Using the relational event model (REM) to investigate the temporal dynamics of animal social networks.
Social dynamics are of fundamental importance in animal societies. Studies on nonhuman animal social systems often aggregate social interaction event data into a single network within a particular time frame. Analysis of the resulting network can provide a useful insight into the overall extent of interaction. However, through aggregation, information is lost about the order in which interactions occurred, and hence the sequences of actions over time. Many research hypotheses relate directly to the sequence of actions, such as the recency or rate of action, rather than to their overall volume or presence. Here, we demonstrate how the temporal structure of social interaction sequences can be quantified from disaggregated event data using the relational event model (REM). We first outline the REM, explaining why it is different from other models for longitudinal data, and how it can be used to model sequences of events unfolding in a network. We then discuss a case study on the European jackdaw, Corvus monedula, in which temporal patterns of persistence and reciprocity of action are of interest, and present and discuss the results of a REM analysis of these data. One of the strengths of a REM analysis is its ability to take into account different ways in which data are collected. Having explained how to take into account the way in which the data were collected for the jackdaw study, we briefly discuss the application of the model to other studies. We provide details of how the models may be fitted in the R statistical software environment and outline some recent extensions to the REM framework.


Influence of CYP2C9 and VKORC1 on patient response to warfarin: a systematic review and meta-analysis.
Warfarin is a highly effective anticoagulant however its effectiveness relies on maintaining INR in therapeutic range. Finding the correct dose is difficult due to large inter-individual variability. Two genes, CYP2C9 and VKORC1, have been associated with this variability, leading to genotype-guided dosing tables in warfarin labeling. Nonetheless, it remains unclear how genotypic information should be used in practice. Navigating the literature to determine how genotype will influence warfarin response in a particular patient is difficult, due to significant variation in patient ethnicity, outcomes investigated, study design, and methodological rigor. Our systematic review was conducted to enable fair and accurate interpretation of which variants affect which outcomes, in which patients, and to what extent. A comprehensive search strategy was applied and 117 studies included. Primary outcomes were stable dose, time to stable dose and bleeding events. Methodological quality was assessed using criteria of Jorgensen and Williamson and data synthesized in meta-analyses using advanced methods. Pooled effect estimates were significant in most ethnic groups for CYP2C9*3 and stable dose (mutant types requiring between 1.1(0.7-1.5) and 2.3 (1.6-3.0)mg/day). Effect estimates were also significant for VKORC1 and stable dose for most ethnicities, although direction differed between asians and non-asians (mutant types requiring between 0.8(0.4-1.3) and 1.5(1.1-1.8)mg/day more in asians and between 1.5(0.7-2.2) and 3.1(2.7-3.6)mg/day less in non-asians). Several studies were excluded due to inadequate data reporting. Assessing study quality highlighted significant variability in methodological rigor. Notably, there was significant evidence of selective reporting, of outcomes and analysis approaches. Genetic associations with warfarin response vary between ethnicities. In order to achieve unbiased estimates in different populations, a high level of methodological rigor must be maintained and studies should report sufficient data to enable inclusion in meta-analyses. We propose minimum reporting requirements, suggest methodological guidelines and provide recommendations for reducing the risk of selective reporting.


Fibrinogen and α1-antitrypsin in COPD exacerbations.
We tested the hypotheses that fibrinogen and α1-antitrypsin are observationally and genetically associated with exacerbations in COPD. We studied 13,591 individuals with COPD from the Copenhagen General Population Study (2003-2013), of whom 6857 were genotyped for FGB -455 (rs1800790, G>A) and FGB -448 (rs4220, G>A) and had plasma fibrinogen measured. Furthermore, 13,405 individuals were genotyped for the SERPINA1 S-allele (rs17580) and the Z-allele (rs28929474) and had measurements of plasma α1-antitrypsin. Exacerbations were defined as hospital admissions or treatments with systemic corticosteroids. We studied observational associations between plasma measurements and exacerbations in Cox regression analyses, associations between genotypes and exacerbations in logistic regression analyses and associations between genetically determined plasma levels and exacerbations in instrumental variable analyses. Elevated fibrinogen and α1-antitrypsin levels were associated with increased risk of exacerbations in COPD, HR=1.14 (1.07 to 1.22, p<0.001) and 1.18 (1.11 to 1.25, p<0.001), respectively, per SD increase. Presence of the Z-allele was associated with increased odds of exacerbations, OR=1.25 (1.05 to 1.48, p=0.01), as was α1-antitrypsin level genetically lowered by the Z-allele, OR=1.07 (1.02 to 1.13, p=0.004), per SD decrease. Fibrinogen elevating genotypes, FGB -455 (AA) and FGB -448 (AA), were not associated with exacerbations, OR=0.96 (0.73 to 1.25, p=0.77) and OR=1.01 (0.75 to 1.33, p=0.90), respectively, and neither was genetically elevated fibrinogen level, OR=1.11 (0.76 to 1.63, p=0.58) per SD increase. Fibrinogen and α1-antitrypsin were observationally associated with increased risk of exacerbations. However, genetically, fibrinogen per se was not associated with exacerbations, while lowered α1-antitrypsin was associated with increased odds of exacerbations.


Vitamin D Status and COVID-19 Clinical Outcomes in Hospitalized Patients.
Context: Populations severely affected by COVID-19 are also at risk for vitamin D deficiency. Common risk factors include older age, chronic illness, obesity, and non-Caucasian race. Vitamin D deficiency has been associated with risk for respiratory infections and failure, susceptibility and response to therapy for enveloped virus infection, and immune-mediated inflammatory reaction.Objective: To test the hypothesis that 25-hydroxyvitamin D[25(OH)D] deficiency is a risk factor for severity of COVID-19 respiratory and inflammatory complications.Design: We examined the relationship between prehospitalization 25(OH)D levels (obtained 1-365 days prior to admission) and COVID-19 clinical outcomes in 700 COVID-19 positive hospitalized patients.Primary Outcomes: Discharge status, mortality, length of stay, intubation status, renal replacement.Secondary Outcomes: Inflammatory markers.Results: 25(OH)D levels were available in 93 patients [25(OH)D:25(IQR:17-33)ng/mL]. Compared to those without 25(OH)D levels, those with measurements did not differ in age, BMI or distribution of sex and race, but were more likely to have comorbidities. Those with 25(OH)D < 20 ng/mL (n = 35) did not differ from those with 25(OH)D ≥ 20 ng/mL in terms of age, sex, race, BMI, or comorbidities. Low 25(OH)D tended to be associated with younger age and lower frequency of preexisting pulmonary disease. There were no significant between-group differences in any outcome. Results were similar in those ≥50 years, in male/female-only cohorts, and when differing 25(OH)D thresholds were used (<15 ng/mL and <30 ng/mL). There was no relationship between 25(OH)D as a continuous variable and any outcome, even after controlling for age and pulmonary disease.Conclusions: These preliminary data do not support a relationship between prehospitalization vitamin D status and COVID-19 clinical outcomes.


ICRP publication 121: radiological protection in paediatric diagnostic and interventional radiology.
Paediatric patients have a higher average risk of developing cancer compared with adults receiving the same dose. The longer life expectancy in children allows more time for any harmful effects of radiation to manifest, and developing organs and tissues are more sensitive to the effects of radiation. This publication aims to provide guiding principles of radiological protection for referring clinicians and clinical staff performing diagnostic imaging and interventional procedures for paediatric patients. It begins with a brief description of the basic concepts of radiological protection, followed by the general aspects of radiological protection, including principles of justification and optimisation. Guidelines and suggestions for radiological protection in specific modalities - radiography and fluoroscopy, interventional radiology, and computed tomography - are subsequently covered in depth. The report concludes with a summary and recommendations. The importance of rigorous justification of radiological procedures is emphasised for every procedure involving ionising radiation, and the use of imaging modalities that are non-ionising should always be considered. The basic aim of optimisation of radiological protection is to adjust imaging parameters and institute protective measures such that the required image is obtained with the lowest possible dose of radiation, and that net benefit is maximised to maintain sufficient quality for diagnostic interpretation. Special consideration should be given to the availability of dose reduction measures when purchasing new imaging equipment for paediatric use. One of the unique aspects of paediatric imaging is with regards to the wide range in patient size (and weight), therefore requiring special attention to optimisation and modification of equipment, technique, and imaging parameters. Examples of good radiographic and fluoroscopic technique include attention to patient positioning, field size and adequate collimation, use of protective shielding, optimisation of exposure factors, use of pulsed fluoroscopy, limiting fluoroscopy time, etc. Major paediatric interventional procedures should be performed by experienced paediatric interventional operators, and a second, specific level of training in radiological protection is desirable (in some countries, this is mandatory). For computed tomography, dose reduction should be optimised by the adjustment of scan parameters (such as mA, kVp, and pitch) according to patient weight or age, region scanned, and study indication (e.g. images with greater noise should be accepted if they are of sufficient diagnostic quality). Other strategies include restricting multiphase examination protocols, avoiding overlapping of scan regions, and only scanning the area in question. Up-to-date dose reduction technology such as tube current modulation, organ-based dose modulation, auto kV technology, and iterative reconstruction should be utilised when appropriate. It is anticipated that this publication will assist institutions in encouraging the standardisation of procedures, and that it may help increase awareness and ultimately improve practices for the benefit of patients.


Non-redox-active lipoate derivates disrupt cancer cell mitochondrial metabolism and are potent anticancer agents in vivo.
We report the analysis of CPI-613, the first member of a large set of analogs of lipoic acid (lipoate) we have investigated as potential anticancer agents. CPI-613 strongly disrupts mitochondrial metabolism, with selectivity for tumor cells in culture. This mitochondrial disruption includes activation of the well-characterized, lipoate-responsive regulatory phosphorylation of the E1α pyruvate dehydrogenase (PDH) subunit. This phosphorylation inactivates flux of glycolysis-derived carbon through this enzyme complex and implicates the PDH regulatory kinases (PDKs) as a possible drug target. Supporting this hypothesis, RNAi knockdown of the PDK protein levels substantially attenuates CPI-613 cancer cell killing. In both cell culture and in vivo tumor environments, the observed strong mitochondrial metabolic disruption is expected to significantly compromise cell survival. Consistent with this prediction, CPI-613 disruption of tumor mitochondrial metabolism is followed by efficient commitment to cell death by multiple, apparently redundant pathways, including apoptosis, in all tested cancer cell lines. Further, CPI-613 shows strong antitumor activity in vivo against human non-small cell lung and pancreatic cancers in xenograft models with low side-effect toxicity.


Provider-initiated testing and counselling programmes in sub-Saharan Africa: a systematic review of their operational implementation.
The routine offer of an HIV test during patient-provider encounters is gaining momentum within HIV treatment and prevention programmes. This review examined the operational implementation of provider-initiated testing and counselling (PITC) programmes in sub-Saharan Africa. PUBMED, EMBASE, Global Health, COCHRANE Library and JSTOR databases were searched systematically for articles published in English between January 2000 and November 2010. Grey literature was explored through the websites of international and nongovernmental organizations. Eligibility of studies was based on predetermined criteria applied during independent screening by two researchers. We retained 44 studies out of 5088 references screened. PITC polices have been effective at identifying large numbers of previously undiagnosed individuals. However, the translation of policy guidance into practice has had mixed results, and in several studies of routine programmes the proportion of patients offered an HIV test was disappointingly low. There were wide variations in the rates of acceptance of the test and poor linkage of those testing positive to follow-up assessments and antiretroviral treatment. The challenges encountered encompass a range of areas from logistics, to data systems, human resources and management, reflecting some of the weaknesses of health systems in the region. The widespread adoption of PITC provides an unprecedented opportunity for identifying HIV-positive individuals who are already in contact with health services and should be accompanied by measures aimed at strengthening health systems and fostering the normalization of HIV at community level. The resources and effort needed to do this successfully should not be underestimated.


The woman who gave birth to a dog Monstrosity and bestiality in Quaestiones Medico-Legales by Paolo Zacchia.
The Italian Paolo Zacchia (1584-1659) is considered one of the fathers of forensic medicine. From a letter sent by the physician and botanist Pietro Castelli, the article seeks to reconstruct the opinions that Zacchia expressed about monsters in his monumental Quaestiones Medico-Legales. Although he did not seem too sure about the possibility that a hybrid could be born from the union of a man and a beast, he believed that God intervened, allowing the birth so that the abomination could be discovered. The opinion of Zacchia is related to the image that people had at the time of the relationship between humans and animals.


Measuring the health-related Sustainable Development Goals in 188 countries: a baseline analysis from the Global Burden of Disease Study 2015.
In September, 2015, the UN General Assembly established the Sustainable Development Goals (SDGs). The SDGs specify 17 universal goals, 169 targets, and 230 indicators leading up to 2030. We provide an analysis of 33 health-related SDG indicators based on the Global Burden of Diseases, Injuries, and Risk Factors Study 2015 (GBD 2015). We applied statistical methods to systematically compiled data to estimate the performance of 33 health-related SDG indicators for 188 countries from 1990 to 2015. We rescaled each indicator on a scale from 0 (worst observed value between 1990 and 2015) to 100 (best observed). Indices representing all 33 health-related SDG indicators (health-related SDG index), health-related SDG indicators included in the Millennium Development Goals (MDG index), and health-related indicators not included in the MDGs (non-MDG index) were computed as the geometric mean of the rescaled indicators by SDG target. We used spline regressions to examine the relations between the Socio-demographic Index (SDI, a summary measure based on average income per person, educational attainment, and total fertility rate) and each of the health-related SDG indicators and indices. In 2015, the median health-related SDG index was 59·3 (95% uncertainty interval 56·8-61·8) and varied widely by country, ranging from 85·5 (84·2-86·5) in Iceland to 20·4 (15·4-24·9) in Central African Republic. SDI was a good predictor of the health-related SDG index (r2=0·88) and the MDG index (r2=0·92), whereas the non-MDG index had a weaker relation with SDI (r2=0·79). Between 2000 and 2015, the health-related SDG index improved by a median of 7·9 (IQR 5·0-10·4), and gains on the MDG index (a median change of 10·0 [6·7-13·1]) exceeded that of the non-MDG index (a median change of 5·5 [2·1-8·9]). Since 2000, pronounced progress occurred for indicators such as met need with modern contraception, under-5 mortality, and neonatal mortality, as well as the indicator for universal health coverage tracer interventions. Moderate improvements were found for indicators such as HIV and tuberculosis incidence, minimal changes for hepatitis B incidence took place, and childhood overweight considerably worsened. GBD provides an independent, comparable avenue for monitoring progress towards the health-related SDGs. Our analysis not only highlights the importance of income, education, and fertility as drivers of health improvement but also emphasises that investments in these areas alone will not be sufficient. Although considerable progress on the health-related MDG indicators has been made, these gains will need to be sustained and, in many cases, accelerated to achieve the ambitious SDG targets. The minimal improvement in or worsening of health-related indicators beyond the MDGs highlight the need for additional resources to effectively address the expanded scope of the health-related SDGs. Bill & Melinda Gates Foundation.


Growth of micro-organisms in gel-stabilized two-dimensional diffusion gradient systems.
The Szybalski wedge plate technique was modified to generate two-dimensional diffusion gradients for two environmental variables: pH value and NaCl concentration were selected in this study. After experimentation, pH values chosen ranged from 3.9 to 8.1 and salt concentrations from 23 to 79 g 1(-1). The pH gradients were slightly sigmoidal whilst the salt gradients were approximately linear. The reproducibility of the technique was assessed and found to be satisfactory in replicate growth experiments. A wide range of growth patterns was observed for a large variety of different bacterial types. The growth boundary and the pattern details are sufficiently distinct to suggest that the technique can distinguish between closely related species or strains.


Provider Perception of Pharmacy Services in the Patient-Centered Medical Home.
Despite the positive data on clinical outcomes, cost savings, and provider experience, no study has surveyed providers to evaluate what pharmacy services they find to be worthwhile. To determine what clinical, cost/access, and educational pharmacy services providers in a patient-centered medical home (PCMH) consider worthwhile and the perceived barriers to successful pharmacist incorporation. A cross-sectional online survey was distributed to primary care physicians, nurse practitioners, and physician assistants in a PCMH physician group. The survey response rate was 78%. Top-tier clinical services were identified as medication counseling, reconciliation, adherence assessment, polypharmacy assessment, and drug information. Formulary review was the only top-tier cost- or access-related service. Top-tier educational services included new black-boxed warnings, drug market withdrawals, and new drug reviews. Ninety-one percent of providers were comfortable referring to a pharmacist for diabetes medication selection and dose titration, but no other disease state eclipsed 75%. More than twice as many providers found the pharmacy service to be very or extremely valuable when the pharmacist is physically located in the office versus virtual interactions (70% vs 34%). Top-tier clinical, cost/access, and educational services considered worthwhile by providers in a PCMH have been identified. In addition to these services, when developing or evaluating a pharmacy service, special attention should be paid to provider preference for physical location in the office and perceived barriers to the pharmacist availability, concern over complex disease management competency and patient confusion as to the role of the pharmacist.


Efficacy and safety of continuous hemodiafiltration for acute decompensated heart failure.
The mortality of heart failure patients with renal insufficiency is high, and these patients tend to develop diuretic resistance. Under these conditions, continuous hemodiafiltration (CHDF) is a possible alternative volume reduction therapy to diuretics. However, its efficacy and safety are not clear. Between April 2005 and March 2008, 248 patients with acute decompensated heart failure were admitted to the CCU of Kyoto City Hospital. Of those patients, 31 (20 volume overloaded heart failure, 11 cardiogenic shock) received CHDF therapy, and their weight loss, acute hemodynamic changes, and clinical outcome were assessed to evaluate the efficacy and safety of CHDF therapy. CHDF was performed for 6.5 +/- 6.5 days. There was no significant change in acute hemodynamics after CHDF initiation. In the volume overloaded heart failure (VH) group, significant weight loss was observed at 24 hours and 48 hours after CHDF initiation (P < 0.001). In-hospital mortality of the VH group and cardiogenic shock (CS) group were 10.0% and 54.5%, respectively. CHDF for acute decompensated heart failure (ADHF) is a safe, effective, and reliable volume reduction therapy for volume overloaded heart failure. Further investigation is required to assess the effectiveness of CHDF for cardiogenic shock.


On the resilience of remote traumatic memories against exposure therapy-mediated attenuation.
How to attenuate traumatic memories has long been the focus of intensive research efforts, as traumatic memories are extremely persistent and heavily impinge on the quality of life. Despite the fact that traumatic memories are often not readily amenable to immediate intervention, surprisingly few studies have investigated treatment options for remote traumata in animal models. The few that have unanimously concluded that exposure therapy-based approaches, the most successful behavioral intervention for the attenuation of recent forms of traumata in humans, fail to effectively reduce remote fear memories. Here, we provide an overview of these animal studies with an emphasis on why remote traumatic memories might be refractory to behavioral interventions: A lack of neuroplasticity in brain areas relevant for learning and memory emerges as a common denominator of such resilience. We then outline the findings of a recent study in mice showing that by combining exposure therapy-like approaches with small molecule inhibitors of histone deacetylases (HDACis), even remote memories can be persistently attenuated. This pharmacological intervention reinstated neuroplasticity to levels comparable to those found upon successful attenuation of recent memories. Thus, HDACis-or any other agent capable of heightening neuroplasticity-in conjunction with exposure therapy-based treatments might constitute a promising approach to overcome remote traumata.


Identification and comparative analyses of myocardial miRNAs involved in the fetal response to maternal obesity.
Human and animal studies show that suboptimal intrauterine environments lead to fetal programming, predisposing offspring to disease in later life. Maternal obesity has been shown to program offspring for cardiovascular disease (CVD), diabetes, and obesity. MicroRNAs (miRNAs) are small, noncoding RNA molecules that act as key regulators of numerous cellular processes. Compelling evidence links miRNAs to the control of cardiac development and etiology of cardiac pathology; however, little is known about their role in the fetal cardiac response to maternal obesity. Our aim was to sequence and profile the cardiac miRNAs that are dysregulated in the hearts of baboon fetuses born to high fat/high fructose-diet (HFD) fed mothers for comparison with fetal hearts from mothers eating a regular diet. Eighty miRNAs were differentially expressed. Of those, 55 miRNAs were upregulated and 25 downregulated with HFD. Twenty-two miRNAs were mapped to human; 14 of these miRNAs were previously reported to be dysregulated in experimental or human CVD. We used an Ingenuity Pathway Analysis to integrate miRNA profiling and bioinformatics predictions to determine miRNA-regulated processes and genes potentially involved in fetal programming. We found a correlation between miRNA expression and putative gene targets involved in developmental disorders and CVD. Cellular death, growth, and proliferation were the most affected cellular functions in response to maternal obesity. Thus, the current study reveals significant alterations in cardiac miRNA expression in the fetus of obese baboons. The epigenetic modifications caused by adverse prenatal environment may represent one of the mechanisms underlying fetal programming of CVD.


Male adolescent sexual and reproductive health care.
Male adolescents' sexual and reproductive health needs often go unmet in the primary care setting. This report discusses specific issues related to male adolescents' sexual and reproductive health care in the context of primary care, including pubertal and sexual development, sexual behavior, consequences of sexual behavior, and methods of preventing sexually transmitted infections (including HIV) and pregnancy. Pediatricians are encouraged to address male adolescent sexual and reproductive health on a regular basis, including taking a sexual history, performing an appropriate examination, providing patient-centered and age-appropriate anticipatory guidance, and delivering appropriate vaccinations. Pediatricians should provide these services to male adolescent patients in a confidential and culturally appropriate manner, promote healthy sexual relationships and responsibility, and involve parents in age-appropriate discussions about sexual health with their sons.


Integration column: Microfluidic high-throughput screening.
Biology has always been a heavily technology limited field. Burgeoning fields such as systems biology require the development and implementation of new technologies, enabling high-throughput and high-fidelity measurements of large systems. Microfluidics promises to fulfil many of the requirements put forth. Here I will discuss the various approaches employed to date for performing high-throughput screening experiments on-chip, encompassing biochemical, biophysical, and cell-based assays.


Irish exceptionalism? Local food environments and dietary quality.
To explore whether distance to and density of food outlets within the local area have an impact on individual dietary quality, controlling for the socioeconomic characteristics of individuals and their households. An analysis of the Survey of Lifestyle, Attitudes and Nutrition in Ireland (SLÁN), a two-stage clustered sample of 10,364 individuals aged 18+ from the Republic of Ireland. Socioeconomic status was measured using net household income and highest level of education. Diet was assessed via a food frequency questionnaire and the results scored in terms of cardiovascular risk. Food availability was measured in terms of distance to (Euclidean and network) and density of different types of food outlets. Dietary quality was decomposed using fixed effects regression models. There is a pronounced gradient in distances to nearest food store and quality of diet by socioeconomic status. Controlling for individual and household socioeconomic status and demographic characteristics, individuals who live closer to a larger food outlet or who live in an area with a higher density of larger food outlets have a significantly better diet in terms of cardiovascular risk. Studies outside of North America have failed to find that the physical availability of food plays a significant role in socioeconomic gradients in diet and nutrition. This study suggests that food availability in the Republic of Ireland plays a small but statistically significant role in influencing the diets of individuals and communities and, as such, may also influence socioeconomic inequalities in health.


Intact automatic imitation of human and robot actions in autism spectrum disorders.
The existence of a specialized imitation module in humans is hotly debated. Studies suggesting a specific imitation impairment in individuals with autism spectrum disorders (ASD) support a modular view. However, the voluntary imitation tasks used in these studies (which require socio-cognitive abilities in addition to imitation for successful performance) cannot support claims of a specific impairment. Accordingly, an automatic imitation paradigm (a 'cleaner' measure of imitative ability) was used to assess the imitative ability of 16 adults with ASD and 16 non-autistic matched control participants. Participants performed a prespecified hand action in response to observed hand actions performed either by a human or a robotic hand. On compatible trials the stimulus and response actions matched, while on incompatible trials the two actions did not match. Replicating previous findings, the Control group showed an automatic imitation effect: responses on compatible trials were faster than those on incompatible trials. This effect was greater when responses were made to human than to robotic actions ('animacy bias'). The ASD group also showed an automatic imitation effect and a larger animacy bias than the Control group. We discuss these findings with reference to the literature on imitation in ASD and theories of imitation.


Schistosoma kisumuensis n. sp. (Digenea: Schistosomatidae) from murid rodents in the Lake Victoria Basin, Kenya and its phylogenetic position within the S. haematobium species group.
Schistosoma kisumuensis n. sp. is described based on 6 adult males and 2 adult females collected from the circulatory system of 3 murid rodent species, Pelomys isseli, Mastomys natalensis, and Dasymys incomtus. Specimens were collected from a single location, Nyabera Swamp, in Kisumu, Kenya in the Lake Victoria Basin. This new species is morphologically similar to members of the S. haematobium group, currently represented by 8 species parasitizing artiodactyls and primates, including humans. Schistosoma kisumuensis differs from these species by producing relatively small Schistosoma intercalatum-like eggs (135.2 x 52.9 microm) with a relatively small length to width ratio (2.55). Comparison of approximately 3000-base-pair sequences of nuclear rDNA (partial 28S) and mtDNA (partial cox1, nad6, 12S) strongly supports the status of S. kisumuensis as a new species and as a sister species of S. intercalatum. The cox1 genetic distance between these two species (6.3%) is comparable to other pairwise comparisons within the S. haematobium group. Separation of the Congo River and Lake Victoria drainage basins is discussed as a possible factor favoring the origin of this species.


Physical activity, sedentary time and physical capability in early old age: British birth cohort study.
To investigate the associations of time spent sedentary, in moderate-to-vigorous-intensity physical activity (MVPA) and physical activity energy expenditure (PAEE) with physical capability measures at age 60-64 years. Time spent sedentary and in MVPA and, PAEE were assessed using individually calibrated combined heart rate and movement sensing among 1727 participants from the MRC National Survey of Health and Development in England, Scotland and Wales as part of a detailed clinical assessment undertaken in 2006-2010. Multivariable linear regression models were used to examine the cross-sectional associations between standardised measures of each of these behavioural variables with grip strength, chair rise and timed up-&-go (TUG) speed and standing balance time. Greater time spent in MVPA was associated with higher levels of physical capability; adjusted mean differences in each capability measure per 1 standard deviation increase in MVPA time were: grip strength (0.477 kg, 95% confidence interval (CI): 0.015 to 0.939), chair rise speed (0.429 stands/min, 95% CI: 0.093 to 0.764), standing balance time (0.028 s, 95% CI: 0.003 to 0.053) and TUG speed (0.019 m/s, 95% CI: 0.011 to 0.026). In contrast, time spent sedentary was associated with lower grip strength (-0.540 kg, 95% CI: -1.013 to -0.066) and TUG speed (-0.011 m/s, 95% CI: -0.019 to -0.004). Associations for PAEE were similar to those for MVPA. Higher levels of MVPA and overall physical activity (PAEE) are associated with greater levels of physical capability whereas time spent sedentary is associated with lower levels of capability. Future intervention studies in older adults should focus on both the promotion of physical activity and reduction in time spent sedentary.


An Adaptation of the Short-Form Supportive Care Needs Survey Questionnaire (SCNS-SF 34) into Turkish.
In the study, Adaptation of The Short-Form Supportive Care Needs Survey Questionnaire (SCNS-SF 34) into Turkish, examination of its validity and reliability was aimed at. The study was carried out between May and July, 2016 with 170 patients. The socio-demographic and clinical status was analyzed by means of number averages and standard deviation. After language validity, the content validity index was calculated. The split-scale analyses, which are reliability internal consistency tests, were performed with the Cronbach α coefficient and total item correlation. For structure validity, exploratory factor analysis was used. The average age of the patients is 55.53±11.43 years and average time since diagnosis is 5.69±5.06 years. The content validity index of the scale was calculated as 0.83. The Cronbach α coefficient is 0.93. In terms of the item total score correlation, all correlation coefficients except items 18 and 19 were between 0.36 and 0.81 and p<0.001. Items 18 and 19 were excluded. Following the exploratory factor analysis, items 13, 17 and 32 were excluded as their two detected high weight values were below 0.10. The descriptive factor analysis of item 29, four factors with eigenvalues over one and the total variance described by these four values was 68.83%. The factors were determined to be healthcare service and informing, psychology, sexuality and daily life. It was confirmed that the SCNS-SF 29Tr is a valid and reliable means for the Turkish society for the determination of the supportive care needs of breast cancer patients.


A comparison of maternal attitudes to breastfeeding in public and the association with breastfeeding duration in four European countries: results of a cohort study.
There is wide variation in the duration of breastfeeding across Europe which may in part be due to the between-country differences in mothers' and societal attitudes towards breastfeeding in public. The objective of this study was to quantify and compare the maternal attitudes to, and practice of, breastfeeding in public in four European centers and investigate the association with duration of breastfeeding. Participants (n = 389) were mothers recruited from maternity wards of hospitals in Glasgow (Scotland), Stockholm (Sweden), Granada (Spain), and Reggio-Emilia (Italy). Among those who had breastfed, Scottish (adjOR 0.25 [95% CI 0.12-0.50]) and Italian mothers (adjOR 0.30 [95% CI 0.14-0.63]) were significantly less likely than Swedish mothers to have ever breastfed in public. Mothers who had a negative attitude toward breastfeeding in public were less likely to have ever breastfed in public (adjOR 0.05 [95% CI 0.02-0.17]), and those who had never breastfed in public were in turn more likely to discontinue breastfeeding earlier. Perceived social norms may exert a stronger influence on breastfeeding outcomes than a woman's breastfeeding attitudes and knowledge. Differences between European countries in the duration of breastfeeding may be explained in part by differences in societal attitudes to breastfeeding in public.