Zebrafish fgf24 functions with fgf8 to promote posterior mesodermal development.
Fibroblast growth factor (Fgf) signaling plays an important role during development of posterior mesoderm in vertebrate embryos. Blocking Fgf signaling by expressing a dominant-negative Fgf receptor inhibits posterior mesoderm development. In mice, Fgf8 appears to be the principal ligand required for mesodermal development, as mouse Fgf8 mutants do not form mesoderm. In zebrafish, Fgf8 is encoded by the acerebellar locus, and, similar to its mouse otholog, is expressed in early mesodermal precursors during gastrulation. However, zebrafish fgf8 mutants have only mild defects in posterior mesodermal development, suggesting that it is not the only Fgf ligand involved in the development of this tissue. We report here the identification of an fgf8-related gene in zebrafish, fgf24, that is co-expressed with fgf8 in mesodermal precursors during gastrulation. Using morpholino-based gene inactivation, we have analyzed the function of fgf24 during development. We found that inhibiting fgf24 function alone has no affect on the formation of posterior mesoderm. Conversely, inhibiting fgf24 function in embryos mutant for fgf8 blocks the formation of most posterior mesoderm. Thus, fgf8 and fgf24 are together required to promote posterior mesodermal development. We provide both phenotypic and genetic evidence that these Fgf signaling components interact with no tail and spadetail, two zebrafish T-box transcription factors that are required for the development of all posterior mesoderm. Last, we show that fgf24 is expressed in early fin bud mesenchyme and that inhibiting fgf24 function results in viable fish that lack pectoral fins.


Towards integrating toxicity characterization into environmental studies: case study of bromine in soils.
AbstractPollution from bromine and some of its related compounds is currently unregulated in soil from Russia and other countries, and tools for sound assessment of environmental impacts of bromine contamination are largely missing. Hence, assessing potential implications for humans and ecosystems of bromine soil contamination is urgently needed, which requires the combination of measured soil concentrations from environmental studies and quantified potential toxicity impacts. To address this need, we used data from an experimental study assessing bromine in soils (384 samples) of Tomsk oblast, Russia, starting from measured concentrations obtained by Instrumental Neutron Activation Analysis in an earlier study. From these data, we calculated the bromine mass in soils and used these as starting point to characterize related cumulative impacts on human health and ecosystems in the Tomsk region, using a global scientific consensus model for screening-level comparative toxicity characterization of chemical emissions. Results show that the combination of sampling methodology with toxicity characterization techniques presents a new approach to be used in environmental studies aimed at environmental assessment and analysis of a territory. Our results indicate that it is important to account for substance-specific chemical reaction pathways and transfer processes, as well as to consider region-specific environmental characteristics. Our approach will help complement environmental assessment results with environmental sustainability elements, to consider potential tradeoffs in impacts, related to soil pollution, in support of improved emission and pollution reduction strategies.


The impact of sarcopenic obesity on knee and hip osteoarthritis: a scoping review.
The progressive, debilitating nature of knee and hip osteoarthritis can result in severe, persistent pain and disability, potentially leading to a need for total joint arthroplasty (TJA) in end-stage osteoarthritis. TJA in adults with obesity is associated with increased surgical risk and prolonged recovery, yet classifying obesity only using body mass index (BMI) precludes distinction of obesity phenotypes and their impact on surgical risk and recovery. The sarcopenic obesity phenotype, characterized by high adiposity and low skeletal muscle mass, is associated with higher infection rates, poorer function, and slower recovery after surgery in other clinical populations, but not thoroughly investigated in osteoarthritis. The rising prevalence and impact of this phenotype demands further attention in osteoarthritis treatment models of care, particularly as osteoarthritis-related pain, disability, and current treatment practices may inadvertently be influencing its development. A scoping review was used to examine the extent of evidence of sarcopenic obesity in adults with hip or knee osteoarthritis. Medline, CINAHL, Web of Science and EMBASE were systematically searched from inception to December 2017 with keywords and subject headings related to obesity, sarcopenia and osteoarthritis. Eleven studies met inclusion criteria, with indications that muscle weakness, low skeletal muscle mass or sarcopenia are present alongside obesity in this population, potentially impacting therapeutic outcomes, and TJA surgical risk and recovery. Consideration of sarcopenic obesity should be included in osteoarthritis patient assessments.


Effect of evidence-based cardiac drug therapy on mortality in patients with acute coronary syndrome: Findings from the Gulf COAST registry.
To evaluate the prevalence and impact of the prescribing of an evidence-based cardiac medication (EBM) combination on 1-month, 6-months, and 12-months all-cause mortality in patients with acute coronary syndrome (ACS). Data were analyzed from 3681 consecutive patients diagnosed with ACS admitted to 29 hospitals in 4 Middle Eastern countries from January 2012 to January 2013. The EBM combination consisted of concurrent prescribing of an antiplatelet therapy, angiotensin-converting enzyme inhibitor (ACEI) or angiotensin II receptor blocker (ARB), β-blocker, and a statin, at hospital discharge. Analyses were performed using univariate and multivariate statistical techniques. The overall mean age of the cohort was 60 ± 13 years, 66% (n = 2436) were males. In all, 69% (n = 2542) of the patients received the quadruple EBM combination at discharge. Two-way interactions between EBM and age (P = 0.824), EBM and GRACE risk score (P = 0.873) and between EBM and discharge diagnosis (P = 0.836) were all not statistically significant. Adjusting for demographic and clinical characteristics, the prescribing of EBM combination was associated with significantly lower cumulative all-cause mortality at 1-month (adjusted OR (aOR), 0.43; 95% confidence interval (CI): 0.24-0.79; P = 0.007), which persisted at 6-months (aOR, 0.52; 95% CI: 0.38-0.72; P < 0.001) and at 12-months of follow-up (aOR, 0.58; 95% CI: 0.44-0.75; P < 0.001) posthospital discharge. Among patients discharged after an ACS event, concurrent EBM prescribing was associated with lower all-cause mortality that persists for up to 12-months posthospital discharge. The relative benefits of EBMs were also consistent across age, GRACE risk score, and discharge diagnosis.


Knowledge, attitude, and practice about malaria: Socio-demographic implications for malaria control in rural Ghana.
Despite continuing international attention to malaria prevention, the disease remains a global public health problem. We investigated socio-demographic factors influencing knowledge, attitudes, and practices about malaria in rural Ghana. Our survey looked at 354 households. Mean knowledge score was higher among individuals with a history of volunteers having visited their households to educate them about malaria; families with 4-6 members; and males. Households with at least one under-five-aged child also had significantly higher knowledge scores. Households with at least one pregnant woman evinced a positive attitude towards malaria prevention. National malaria control strategies have achieved positive results in the fight against malaria. Nonetheless, multipronged community-based health strategies that integrate malaria programs and population growth control initiatives may be able to reach by 2030 the sustainable development goal of eliminating malaria.


Monitoring pandemic influenza A(H1N1) vaccination coverage in Germany 2009/10 - results from thirteen consecutive cross-sectional surveys.
To monitor pandemic influenza A(H1N1) vaccine uptake during the vaccination campaign in Germany 2009/10, thirteen consecutive cross-sectional telephone-surveys were performed between November 2009 and April 2010. In total 13,010 household-interviews were conducted. Vaccination coverage in persons >14 years of age remained low, both in the general population (8.1%; 95%CI: 7.4-8.8) and in specific target groups such as healthcare workers and individuals with underlying chronic diseases (12.8%; 95%CI: 11.4-14.4). Previous vaccination against seasonal influenza was a main factor independently associated with pandemic influenza vaccination (Odds ratio=8.8; 95%CI: 7.2-10.8). The campaign failed to reach people at risk who were not used to receive their annual seasonal influenza shot.


Oral acyclovir in acute herpes zoster.
Oral acyclovir at a dose of 800 mg five times daily for seven days was compared with placebo in a randomised double blind trial conducted at three centres in the United Kingdom. The study group comprised 205 elderly immune competent patients suffering from herpes zoster who were entered within 72 hours of the onset of rash. Acyclovir significantly reduced the times to arrest of new lesion formation (p = 0.005), loss of vesicles (p less than 0.001), and full crusting (p = 0.02) in those patients entered within 48 hours of the onset of rash. In addition, there was a significant reduction in pain during treatment with acyclovir as compared with placebo (p = 0.008). Of the patients with severe pain on entry, 40% (10/25) of those treated with acyclovir had no or only mild pain at the end of treatment, whereas in the placebo group all had residual moderate or severe pain (p less than 0.001). No clinically important adverse effects of acyclovir were reported. Oral acyclovir may modify acute herpes zoster and reduce pain.


Transgenic Cotton Plants Expressing Double-stranded RNAs Target HMG-CoA Reductase (HMGR) Gene Inhibits the Growth, Development and Survival of Cotton Bollworms.
RNA interference (RNAi) has been developed as a powerful technique in the research of functional genomics as well as plant pest control. In this report, double-stranded RNAs (dsRNA) targeting 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR) gene, which catalyze a rate-limiting enzymatic reaction in the mevalonate pathway of juvenile hormone (JH) synthesis in cotton bollworm, was expressed in cotton plants via Agrobacterium tumefaciens-mediated transformation. PCR and Sothern analysis revealed the integration of HMGR gene into cotton genome. RT-PCR and qRT-PCR confirmed the high transcription level of dsHMGR in transgenic cotton lines. The HMGR expression both in transcription and translation level was significantly downregulated in cotton bollworms (helicoverpa armigera) larvae after feeding on the leaves of HMGR transgenic plants. The transcription level of HMGR gene in larvae reared on transgenic cotton leaves was as much as 80.68% lower than that of wild type. In addition, the relative expression level of vitellogenin (Vg, crucial source of nourishment for offspring embryo development) gene was also reduced by 76.86% when the insect larvae were fed with transgenic leaves. The result of insect bioassays showed that the transgenic plant harboring dsHMGR not only inhibited net weight gain but also delayed the growth of cotton bollworm larvae. Taken together, transgenic cotton plant expressing dsRNAs successfully downregulated HMGR gene and impaired the development and survival of target insect, which provided more option for plant pest control.


Radio-luminescence spectral features and fast emission in hafnium dioxide nanocrystals.
In this work, we investigate the optical properties of hafnium dioxide nanocrystals, upon X-ray irradiation, looking for spectral evolution following thermal treatments in air up to 1000 °C that modify the crystal size as well as their point defect concentrations. Radio-luminescence measurements from 10 K up to room temperature reveal a rich and evolving picture of the optical features. A complete spectral analysis of the broad luminescence spectra reveals the presence of several emission components in the visible and UV regions. The lower energy components peaking at 2.1, 2.5, and 2.9 eV are characterized by a thermal quenching energy of 0.08 eV, while the corresponding value for the UV bands at 4.1 and 4.7 eV is close to 0.23 eV. We tentatively assign the components ranging from 2 to 3 eV to the presence of optically active defects of an intrinsic nature, together with the occurrence of titanium impurities; conversely, the bands at higher energies are likely to be of an excitonic nature. The comparison with previous photo-luminescence studies allows evidencing characteristic differences between the features of luminescence emissions caused by intra-centre excitation and those occurring under ionizing irradiation. Finally, scintillation measurements in the visible range reveal the existence of a fast decay in the nanosecond time scale for the smallest hafnia nanocrystals. This study offers a clear description of HfO2 luminescence characteristics upon excitation by X-rays and can lead to a better comprehension of the structure-property relationship at the nanoscale in metal oxides.


Identification and analysis of the interaction between Edc3 and Dcp2 in Saccharomyces cerevisiae.
Cap hydrolysis is a critical control point in the life of eukaryotic mRNAs and is catalyzed by the evolutionarily conserved Dcp1-Dcp2 complex. In Saccharomyces cerevisiae, decapping is modulated by several factors, including the Lsm family protein Edc3, which directly binds to Dcp2. We show that Edc3 binding to Dcp2 is mediated by a short peptide sequence located C terminal to the catalytic domain of Dcp2. This sequence is required for Edc3 to stimulate decapping activity of Dcp2 in vitro, for Dcp2 to efficiently accumulate in P-bodies, and for efficient degradation of the RPS28B mRNA, whose decay is enhanced by Edc3. In contrast, degradation of YRA1 pre-mRNA, another Edc3-regulated transcript, occurs independently from this region, suggesting that the effect of Edc3 on YRA1 is independent of its interaction with Dcp2. Deletion of the sequence also results in a subtle but significant defect in turnover of the MFA2pG reporter transcript, which is not affected by deletion of EDC3, suggesting that the region affects some other aspect of Dcp2 function in addition to binding Edc3. These results raise a model for Dcp2 recruitment to specific mRNAs where regions outside the catalytic core promote the formation of different complexes involved in mRNA decapping.


Intratumoral delivery of tavokinogene telseplasmid yields systemic immune responses in metastatic melanoma patients.
Interleukin 12 (IL-12) is a pivotal regulator of innate and adaptive immunity. We conducted a prospective open-label, phase II clinical trial of electroporated plasmid IL-12 in advanced melanoma patients (NCT01502293). Patients with stage III/IV melanoma were treated intratumorally with plasmid encoding IL-12 (tavokinogene telseplasmid; tavo), 0.5 mg/ml followed by electroporation (six pulses, 1500 V/cm) on days 1, 5, and 8 every 90 days in the main study and additional patients were treated in two alternative schedule exploration cohorts. Correlative analyses for programmed death-ligand 1 (PD-L1), flow cytometry to assess changes in immune cell subsets, and analysis of immune-related gene expression were carried out on pre- and post-treatment samples from study patients, as well as from additional patients treated during exploration of additional dosing schedules beyond the pre-specified protocol dosing schedule. Response was measured by study-specific criteria to maximize detection of latent and potentially transient immune responses in patients with multiple skin lesions and toxicities were graded by the Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v4.0). The objective overall response rate was 35.7% in the main study (29.8% in all cohorts), with a complete response rate of 17.9% (10.6% in all cohorts). The median progression-free survival in the main study was 3.7 months while the median overall survival was not reached at a median follow up of 29.7 months. A total of 46% of patients in all cohorts with uninjected lesions experienced regression of at least one of these lesions and 25% had a net regression of all untreated lesions. Transcriptomic and immunohistochemistry analysis showed that immune activation and co-stimulatory transcripts were up-regulated but there was also increased adaptive immune resistance. Intratumoral Tavo was well tolerated and led to systemic immune responses in advanced melanoma patients. While tumor regression and increased immune infiltration were observed in treated as well as untreated/distal lesions, adaptive immune resistance limited the response.


Pediatric Corneal Structural Development During Childhood Characterized by Ultrasound Biomicroscopy.
To quantitatively describe the structural corneal changes from infancy to early adulthood using ultrasound biomicroscopy. In this prospective study, 168 ultrasound biomicroscopy images were obtained from 24 healthy eyes of 24 patients who consented and enrolled in the Pediatric Anterior Segment Imaging Innovation Study. Their ages ranged from birth to 26 years. An established ultrasound biomicroscopy imaging protocol including seven views of one eye per patient were obtained and measured using ImageJ software (National Institutes of Health). Twelve corneal structural parameters were measured. Means were compared between younger and older groups. Among the 12 measured structures, 5 demonstrated statistically significant differences (P < .05) between patients younger than 1 year and patients older than 1 year. The mean values for corneal cross-sectional width and length, central corneal thickness, and radii of curvature (anterior and posterior) were significantly different in patients younger than 1 year. Curvature and limbus-to-limbus dimensions changed more dramatically than thickness and tissue density. When comparing the youngest to oldest subgroups, anterior curvature flattened (6.14 to 7.55 radius), posterior curvature flattened (5.53 to 6.72 radius), angle-to-angle distance increased (8.93 to 11.40 mm), and endothelial cross-sectional distance increased (10.63 to 13.61 mm). Pediatric corneal structures change with age. The most significant changes occur in the first months of life, with additional changes later in childhood. This study further demonstrates the importance of age in pediatric corneal imaging analysis. [J Pediatr Ophthalmol Strabismus. 2020;57(4):238-245.].


A study to look at hormonal absorption of progesterone cream used in conjunction with transdermal estrogen.
Natural progesterone creams are gaining popularity as a possible treatment for menopausal symptoms, and many women may be using them with estrogen. We planned to evaluate, using an open plan study, the systemic absorption of a combination of transdermal estrogen and progesterone. Women applied transdermal progesterone 40 mg and transdermal estrogen 1 mg daily over 48 weeks. Women were assessed at intervals of 12 weeks. Significant increases in plasma levels of progesterone and estradiol were seen after 12 weeks, although only low plasma progesterone levels were found (median 2.5 nmol/l) and no further increase was noted over the remainder of the study period. A significant correlation was found between plasma levels of the two hormone (r = 0.315, p = 0.045). Women reported significant reductions in menopausal symptoms, as measured by the Green Climacteric Scale, after 24 and 48 weeks of combined treatment. There may be similar mechanisms of absorption of the two hormones, although the doses used in our study produced sub-luteal levels of progesterone. There was no evidence of accumulation of progesterone with time, and further study is needed to assess the efficacy and safety of this combination of hormones.


Review: Synovial Cell Metabolism and Chronic Inflammation in Rheumatoid Arthritis.
Metabolomic studies of body fluids show that immune-mediated inflammatory diseases such as rheumatoid arthritis (RA) are associated with metabolic disruption. This is likely to reflect the increased bioenergetic and biosynthetic demands of sustained inflammation and changes in nutrient and oxygen availability in damaged tissue. The synovial membrane lining layer is the principal site of inflammation in RA. Here, the resident cells are fibroblast-like synoviocytes (FLS) and synovial tissue macrophages, which are transformed toward overproduction of enzymes that degrade cartilage and bone and cytokines that promote immune cell infiltration. Recent studies have shown metabolic changes in both FLS and macrophages from RA patients, and these may be therapeutically targetable. However, because the origins and subset-specific functions of synoviocytes are poorly understood, and the signaling modules that control metabolic deviation in RA synovial cells are yet to be explored, significant additional research is needed to translate these findings to clinical application. Furthermore, in many inflamed tissues, different cell types can forge metabolic collaborations through solute carriers in their membranes to meet a high demand for energy or biomolecules. Such relationships are likely to exist in the synovium and have not been studied. Finally, it is not yet known whether metabolic change is a consequence of disease or whether primary changes to cellular metabolism might underlie or contribute to the pathogenesis of early-stage disease. In this review article, we collate what is known about metabolism in synovial tissue cells and highlight future directions of research in this area.


The greener the better? Does neighborhood greenness buffer the effects of stressful life events on externalizing behavior in late adolescence?
We tested whether neighborhood greenness is a promotive and/or a protective factor in the development of adolescent externalizing behavior problems and explored a possible mechanism of its effects via respiratory sinus arrhythmia (RSA) recovery after stress. Data from a longitudinal multi-method study on adolescents (N = 715) was used. Result showed that neighborhood greenness was neither a promotive nor a protective factor. However, adolescents who reported more stressful life events showed more externalizing behavior and -contrary to our expectation- this effect was stronger for adolescents who grew up in greener neighborhoods (vs. less green neighborhoods).


Molecules, muscles, and machines: universal performance characteristics of motors.
Animal- and human-made motors vary widely in size and shape, are constructed of vastly different materials, use different mechanisms, and produce an enormous range of mass-specific power. Despite these differences, there is remarkable consistency in the maximum net force produced by broad classes of animal- and human-made motors. Motors that use force production to accomplish steady translational motion of a load (myosin, kinesin, dynein, and RNA polymerase molecules, muscle cells, whole muscles, winches, linear actuators, and rockets) have maximal force outputs that scale as the two-thirds power of mass, i.e., with cross-sectional area. Motors that use cyclical motion to generate force and are more subject to multiaxial stress and vibration have maximal force outputs that scale as a single isometric function of motor mass with mass-specific net force output averaging 57 N x kg(-1) (SD = 14). Examples of this class of motors includes flying birds, bats, and insects, swimming fish, various taxa of running animals, piston engines, electric motors, and all types of jets. Dependence of force production and stress resistance on cross-sectional area is well known, but the isometric scaling and common upper limit of mass-specific force production by cyclical motion motors has not been recognized previously and is not explained by an existing body of theory. Remarkably, this finding indicates that most of the motors used by humans and animals for transportation have a common upper limit of mass-specific net force output that is independent of materials and mechanisms.


A Pathogen-Responsive Leucine Rich Receptor Like Kinase Contributes to Fusarium Resistance in Cereals.
Receptor-like kinases form the largest family of receptors in plants and play an important role in recognizing pathogen-associated molecular patterns and modulating the plant immune responses to invasive fungi, including cereal defenses against fungal diseases. But hitherto, none have been shown to modulate the wheat response to the economically important Fusarium head blight (FHB) disease of small-grain cereals. Homologous genes were identified on barley chromosome 6H (HvLRRK-6H) and wheat chromosome 6DL (TaLRRK-6D), which encode the characteristic domains of surface-localized receptor like kinases. Gene expression studies validated that the wheat TaLRRK-6D is highly induced in heads as an early response to both the causal pathogen of FHB disease, Fusarium graminearum, and its' mycotoxic virulence factor deoxynivalenol. The transcription of other wheat homeologs of this gene, located on chromosomes 6A and 6B, was also up-regulated in response to F. graminearum. Virus-induced gene silencing (VIGS) of the barley HvLRRK-6H compromised leaf defense against F. graminearum. VIGS of TaLRRK-6D in two wheat cultivars, CM82036 (resistant to FHB disease) and cv. Remus (susceptible to FHB), confirmed that TaLRRK-6D contributes to basal resistance to FHB disease in both genotypes. Although the effect of VIGS did not generally reduce grain losses due to FHB, this experiment did reveal that TaLRRK-6D positively contributes to grain development. Further gene expression studies in wheat cv. Remus indicated that VIGS of TaLRRK-6D suppressed the expression of genes involved in salicylic acid signaling, which is a key hormonal pathway involved in defense. Thus, this study provides the first evidence of receptor like kinases as an important component of cereal defense against Fusarium and highlights this gene as a target for enhancing cereal resistance to FHB disease.


Effect of potato fiber on survival of Lactobacillus species at simulated gastric conditions and composition of the gut microbiota in vitro.
Potato fiber is a side product in starch manufacturing rich in dietary fibers such as pectin, cellulose, hemicellulose and resistant starch. So far, the beneficial properties of potato fiber have been poorly characterized. This study investigated the effect of FiberBind 400, a commercial potato fiber product, on survival of probiotic Lactobacillus strains at simulated gastric conditions and on the composition and metabolic activity of the gut microbiota, using the TIM-2 colon model. Resistant starch and native starch from potato were used as reference substrates. FiberBind 400 had an ability to improve survival of the four tested strains, Lactobacillus fermentum PCC®, L. rhamnosus LGG®, L. reuteri RC-14® and L. paracasei F-19® in a strain-dependent way. The highest effect was observed for L. fermentum PCC® and L. rhamnosus LGG®. The effect of starches on bacterial survival was insignificant. Composition of the fecal microbiota in TIM-2 fermentations was assessed by high-throughput sequencing of 16S rRNA gene amplicon. Fermentation of FiberBind 400 resulted in more diverse microbial communities compared to starches. Changes in microbial abundances specifically mediated by FiberBind 400, included increases in the genera Lachnospira, Butyrivibrio, Mogibacterium, Parabacteroides, Prevotella and Desulfovibrio, and the species B. ovatus, as well as decreases in Ruminococcus torques and unassigned Ruminococcus spp. Shifts in other bacterial populations, such as increased abundances of Oscillospira, Enterococcus, Bacteroidales, Citrobacter, along with reduction of Roseburia, Ruminococcus, and Faecalibacterium prausnitzii were not significantly different between the substrates. Cumulative production of individual short-chain fatty acids was similar between potato fiber and starches. The study demonstrated that FiberBind 400 had a potential to protect probiotic Lactobacillus strains during the passage through the gastrointestinal tract and selectively modulate the gut bacterial populations. This knowledge can support application of potato fiber as a functional food ingredient with added biological benefits.


The Efficacy of the Wee1 Inhibitor MK-1775 Combined with Temozolomide Is Limited by Heterogeneous Distribution across the Blood-Brain Barrier in Glioblastoma.
Wee1 regulates key DNA damage checkpoints, and in this study, the efficacy of the Wee1 inhibitor MK-1775 was evaluated in glioblastoma multiforme (GBM) xenograft models alone and in combination with radiation and/or temozolomide. In vitro MK-1775 efficacy alone and in combination with temozolomide, and the impact on DNA damage, was analyzed by Western blotting and γH2AX foci formation. In vivo efficacy was evaluated in orthotopic and heterotopic xenografts. Drug distribution was assessed by conventional mass spectrometry (MS) and matrix-assisted laser desorption/ionization (MALDI)-MS imaging. GBM22 (IC50 = 68 nmol/L) was significantly more sensitive to MK-1775 compared with five other GBM xenograft lines, including GBM6 (IC50 >300 nmol/L), and this was associated with a significant difference in pan-nuclear γH2AX staining between treated GBM22 (81% cells positive) and GBM6 (20% cells positive) cells. However, there was no sensitizing effect of MK-1775 when combined with temozolomide in vitro. In an orthotopic GBM22 model, MK-1775 was ineffective when combined with temozolomide, whereas in a flank model of GBM22, MK-1775 exhibited both single-agent and combinatorial activity with temozolomide. Consistent with limited drug delivery into orthotopic tumors, the normal brain to whole blood ratio following a single MK-1775 dose was 5%, and MALDI-MS imaging demonstrated heterogeneous and markedly lower MK-1775 distribution in orthotopic as compared with heterotopic GBM22 tumors. Limited distribution to brain tumors may limit the efficacy of MK-1775 in GBM.


Strong Relation Between Muscle Mass Determined by D3-creatine Dilution, Physical Performance, and Incidence of Falls and Mobility Limitations in a Prospective Cohort of Older Men.
Direct assessment of skeletal muscle mass in older adults is clinically challenging. Relationships between lean mass and late-life outcomes have been inconsistent. The D3-creatine dilution method provides a direct assessment of muscle mass. Muscle mass was assessed by D3-creatine (D3Cr) dilution in 1,382 men (mean age, 84.2 years). Participants completed the Short Physical Performance Battery (SPPB); usual walking speed (6 m); and dual x-ray absorptiometry (DXA) lean mass. Men self-reported mobility limitations (difficulty walking 2-3 blocks or climbing 10 steps); recurrent falls (2+); and serious injurious falls in the subsequent year. Across quartiles of D3Cr muscle mass/body mass, multivariate linear models calculated means for SPPB and gait speed; multivariate logistic models calculated odds ratios for incident mobility limitations or falls. Compared to men in the highest quartile, those in the lowest quartile of D3Cr muscle mass/body mass had slower gait speed (Q1: 1.04 vs Q4: 1.17 m/s); lower SPPB (Q1: 8.4 vs Q4: 10.4 points); greater likelihood of incident serious injurious falls (odds ratio [OR] Q1 vs Q4: 2.49, 95% confidence interval [CI]: 1.37, 4.54); prevalent mobility limitation (OR Q1 vs Q4,: 6.1, 95% CI: 3.7, 10.3) and incident mobility limitation (OR Q1 vs Q4: 2.15 95% CI: 1.42, 3.26); p for trend < .001 for all. Results for incident recurrent falls were in the similar direction (p = .156). DXA lean mass had weaker associations with the outcomes. Unlike DXA lean mass, low D3Cr muscle mass/body mass is strongly related to physical performance, mobility, and incident injurious falls in older men.


Incentivizing biodiversity conservation in artisanal fishing communities through territorial user rights and business model innovation.
Territorial user rights for fisheries are being promoted to enhance the sustainability of small-scale fisheries. Using Chile as a case study, we designed a market-based program aimed at improving fishers' livelihoods while incentivizing the establishment and enforcement of no-take areas within areas managed with territorial user right regimes. Building on explicit enabling conditions (i.e., high levels of governance, participation, and empowerment), we used a place-based, human-centered approach to design a program that will have the necessary support and buy-in from local fishers to result in landscape-scale biodiversity benefits. Transactional infrastructure must be complex enough to capture the biodiversity benefits being created, but simple enough so that the program can be scaled up and is attractive to potential financiers. Biodiversity benefits created must be commoditized, and desired behavioral changes must be verified within a transactional context. Demand must be generated for fisher-created biodiversity benefits in order to attract financing and to scale the market model. Important design decisions around these 3 components-supply, transactional infrastructure, and demand-must be made based on local social-ecological conditions. Our market model, which is being piloted in Chile, is a flexible foundation on which to base scalable opportunities to operationalize a scheme that incentivizes local, verifiable biodiversity benefits via conservation behaviors by fishers that could likely result in significant marine conservation gains and novel cross-sector alliances.


Neuronal development and axon growth are altered by glyphosate through a WNT non-canonical signaling pathway.
The growth and morphological differentiation of neurons are critical events in the establishment of proper neuronal connectivity and functioning. The developing nervous system is highly susceptible to damage caused by exposure to environmental contaminants. Glyphosate-containing herbicides are the most used agrochemicals in the world, particularly on genetically modified plants. Previous studies have demonstrated that glyphosate induces neurotoxicity in mammals. Therefore, its action mechanism on the nervous system needs to be determined. In this study, we report about impaired neuronal development caused by glyphosate exposure. Particularly, we observed that the initial axonal differentiation and growth of cultured neurons is affected by glyphosate since most treated cells remained undifferentiated after 1 day in culture. Although they polarized at 2 days in vitro, they elicited shorter and unbranched axons and they also developed less complex dendritic arbors compared to controls. To go further, we attempted to identify the cellular mechanism by which glyphosate affected neuronal morphology. Biochemical approaches revealed that glyphosate led to a decrease in Wnt5a level, a key factor for the initial neurite development and maturation, as well as inducing a down-regulation of CaMKII activity. This data suggests that the morphological defects would likely be a consequence of the decrease in both Wnt5a expression and CaMKII activity induced by glyphosate. Additionally, these changes might be reflected in a subsequent neuronal dysfunction. Therefore, our findings highlight the importance of establishing rigorous control on the use of glyphosate-based herbicides in order to protect mammals' health.


Activation of nonexpressed endogenous ecotropic murine leukemia virus by transfection of genomic DNA into embryo cells.
We studied the infectivity of endogenous ecotropic murine leukemia virus genomes contained in high-molecular-weight DNA prepared from virus-free cells of the AKR-2B line, and from RF, BALB/c, B6, and (BALB/c x B6)F(1) mouse embryo cells. When DNA prepared from virus-free AKR-2B cells was transfected into NIH-3T3 cells, no virus-positive cultures were observed, a result consistent with previous reports. However, when DNAs from virus-free AKR-2B cells or virus-free cells containing the RF/J or BALB/c ecotropic proviruses were transfected into chicken embryo cells that were then cocultivated with SC-1 (mouse) cells, virus-positive cultures were recovered. The specific infectivities of the AKR provirus(es) contained in virus-free cells and the molecularly cloned Akv-1 provirus were similar when chicken embryo cells were used as primary recipients. Virus-positive cultures were also observed when secondary mouse embryo cells were used as recipients for DNA from virus-free AKR-2B and RF/J cells. The transfected chicken embryo-SC-1 cultures produced XC-positive murine leukemia virus that is N-tropic. Virus-positive recipient cultures were observed 10- to 100-fold more frequently when AKR-2B DNA was used than when BALB/c DNA was used as the donor DNA. Our studies indicate that some nonexpressed ecotropic murine leukemia virus proviruses are activated upon transfection into chicken embryo cells. Such studies suggest that there are different factors governing the expression of murine leukemia virus after transfection into established cell lines (NIH-3T3) and into nonestablished secondary cultures (chicken and mouse).


A polyphenol-rich cranberry extract protects against endogenous exposure to persistent organic pollutants during weight loss in mice.
The dramatic rise in the global occurrence of obesity and associated diseases calls for new strategies to promote weight loss. However, while the beneficial effects of weight loss are well known, rapid loss of fat mass can also lead to the endogenous release of liposoluble molecules with potential harmful effects, such as persistent organic pollutants (POP). The aim of this study was to evaluate the impact of a polyphenol-rich cranberry extract (CE) on POP release and their potential deleterious effects during weight loss of obese mice. C57BL/6 J mice were fed an obesogenic diet with or without a mixture of POP for 12 weeks and then changed to a low-fat diet to induce weight loss and endogenous POP release. The POP-exposed mice were then separated in two groups during weight loss, receiving either CE or the vehicle. Unexpectedly, despite the higher fat loss in the CE-treated group, the circulating levels of POP were not enhanced in these mice. Moreover, glucose homeostasis was further improved during CE-induced weight loss, as revealed by lower fasting glycemia and improved glucose tolerance as compared to vehicle-treated mice. Interestingly, the CE extract also induced changes in the gut microbiota after weight loss in POP-exposed mice, including blooming of Parvibacter, a member of the Coriobacteriaceae family which has been predicted to play a role in xenobiotic metabolism. Our data thus suggests that the gut microbiota can be targeted by polyphenol-rich extracts to protect from increased POP exposure and their detrimental metabolic effects during rapid weight loss.


Efferent inhibition strength is a physiological correlate of hyperacusis in children with autism spectrum disorder.
Autism spectrum disorder (ASD) is a developmental disability that is poorly understood. ASD can influence communication, social interaction, and behavior. Children with ASD often have sensory hypersensitivities, including auditory hypersensitivity (hyperacusis). In adults with hyperacusis who are otherwise neurotypical, the medial olivocochlear (MOC) efferent reflex is stronger than usual. In children with ASD, the MOC reflex has been measured, but without also assessing hyperacusis. We assessed the MOC reflex in children with ASD by measuring the strength of MOC-induced inhibition of transient-evoked otoacoustic emissions (TEOAEs), a noninvasive physiological measure that reflects cochlear amplification. MOC activity was evoked by contralateral noise. Hyperacusis was assessed subjectively on the basis of the children's symptoms. We found a significant correlation between hyperacusis scores and MOC strength in children with ASD. When children were divided into ASD-with-severe-hyperacusis (ASDs), ASD-with-not-severe-hyperacusis (ASDns), and neurotypical (NT) groups, the last two groups had similar hyperacusis and MOC reflexes, whereas the ASDs group, on average, had hyperacusis and MOC reflexes that were approximately twice as strong. The MOC inhibition of TEOAEs averaged larger at all frequencies in the ASDs compared with ASDns and NT groups. The results suggest that the MOC reflex can be used to estimate hyperacusis in children with ASD and might be used to validate future questionnaires to assess hyperacusis. Our results also provide evidence that strong MOC reflexes in children with ASD are associated with hyperacusis and that hyperacusis is a comorbid condition and is not a necessary, integral part of the abnormal neural processing associated with ASD.NEW & NOTEWORTHY Children with autism spectrum disorder (ASD) are a heterogeneous group, some with hyperacusis and some without. Our research shows that hyperacusis can be estimated in children with ASD by using medial olivocochlear (MOC) reflex measurements. By establishing that an objective measure correlates with attributes of hyperacusis, our results enable future work to enable subtyping of children with ASD to provide improved individualized treatments to at-risk children and those without adequate language to describe their hyperacusis symptoms.


A decade of improvements in equity of access to reproductive and maternal health services in Cambodia, 2000-2010.
Despite encouraging reductions in global maternal mortality rates, Millennium Development Goal (MDG) 5 on reducing maternal mortality and achieving universal access to reproductive health remains the most off-track of all MDGs. Furthermore a preoccupation with aggregate coverage statistics masks extensive disparities in health improvements between societal groups. Recent national health indicators for Cambodia highlight impressive improvements, for example, in maternal, infant and child mortality, whilst substantial government commitments have been made since 2000 to address health inequities. It is therefore timely to explore the extent of equity in access to key reproductive and maternal health services in Cambodia and how this has changed over time. Analysis was conducted on three rounds of Demographic and Health Survey data from 2000, 2005 and 2010. Outcome variables comprised utilisation of six reproductive and maternal health services--antenatal care, skilled birth attendance, facility-based delivery, postnatal care, met need for family planning and abortion by skilled provider. Four equity measures were calculated--equity gaps, equity ratios, concentration curves and concentration indices. Household assets were used to create the social-stratification variable, using principal components analysis. Coverage levels of all six services improved over the decade. Coverage improvements were greatest amongst wealthier quintiles of the population, although poorer quintiles also increased use of services. Critically, inequity in service use of all services dramatically reduced over time, except for postnatal care where inequity increased slightly. However, in 2010 inequity in service use remained favouring wealthier quintiles, greatest in use of skilled birth attendance and facility-based delivery, though the magnitude of inequity was substantially reduced compared to 2000. Met need for family planning was almost perfectly equitable in 2010. Cambodia has made impressive improvements in overall coverage of reproductive and maternal health services over the last decade, and also in the distribution of their use across wealth quintiles. A range of pro-poor health financing and supply-side policies as well as non-health factors may have contributed to these achievements. Further research will explore specific schemes qualitatively and quantitatively to assess their impact on equity and service use.


Cryoprecipitate: an outmoded treatment?
Cryoprecipitate is an allogeneic blood product prepared from human plasma. It contains factors VIII, von Willebrand factor (vWF), fibrinogen, fibronectin and factor XIII. Its use was first described in the 1960s for treatment of patients with factor VIII deficiency. It has also been used to treat patients with congenital hypofibrinogenaemia. Now, the most common use of cryoprecipitate is fibrinogen replacement in patients with acquired hypofibrinogenaemia and bleeding. Despite almost 50 years of use, evidence of efficacy is limited. This review provides an overview of the history of cryoprecipitate use, the current debates on the use of this product and future developments.


Full-length human mutant huntingtin with a stable polyglutamine repeat can elicit progressive and selective neuropathogenesis in BACHD mice.
To elucidate the pathogenic mechanisms in Huntington's disease (HD) elicited by expression of full-length human mutant huntingtin (fl-mhtt), a bacterial artificial chromosome (BAC)-mediated transgenic mouse model (BACHD) was developed expressing fl-mhtt with 97 glutamine repeats under the control of endogenous htt regulatory machinery on the BAC. BACHD mice exhibit progressive motor deficits, neuronal synaptic dysfunction, and late-onset selective neuropathology, which includes significant cortical and striatal atrophy and striatal dark neuron degeneration. Power analyses reveal the robustness of the behavioral and neuropathological phenotypes, suggesting BACHD as a suitable fl-mhtt mouse model for preclinical studies. Additional analyses of BACHD mice provide novel insights into how mhtt may elicit neuropathogenesis. First, unlike previous fl-mhtt mouse models, BACHD mice reveal that the slowly progressive and selective pathogenic process in HD mouse brains can occur without early and diffuse nuclear accumulation of aggregated mhtt (i.e., as detected by immunostaining with the EM48 antibody). Instead, a relatively steady-state level of predominantly full-length mhtt and a small amount of mhtt N-terminal fragments are sufficient to elicit the disease process. Second, the polyglutamine repeat within fl-mhtt in BACHD mice is encoded by a mixed CAA-CAG repeat, which is stable in both the germline and somatic tissues including the cortex and striatum at the onset of neuropathology. Therefore, our results suggest that somatic repeat instability does not play a necessary role in selective neuropathogenesis in BACHD mice. In summary, the BACHD model constitutes a novel and robust in vivo paradigm for the investigation of HD pathogenesis and treatment.


A qualitative analysis of environmental policy and children's health in Mexico.
Since Mexico's joining the North American Free Trade Agreement (NAFTA) and the Organization for Economic Cooperation and Development (OECD) in 1994, it has witnessed rapid industrialization. A byproduct of this industrialization is increasing population exposure to environmental pollutants, of which some have been associated with childhood disease. We therefore identified and assessed the adequacy of existing international and Mexican governance instruments and policy tools to protect children from environmental hazards. We first systematically reviewed PubMed, the Mexican legal code and the websites of the United Nations, World Health Organization, NAFTA and OECD as of July 2007 to identify the relevant governance instruments, and analyzed the approach these instruments took to preventing childhood diseases of environmental origin. Secondly, we interviewed a purposive sample of high-level government officials, researchers and non-governmental organization representatives, to identify their opinions and attitudes towards children's environmental health and potential barriers to child-specific protective legislation and implementation. We identified only one policy tool describing specific measures to reduce developmental neurotoxicity and other children's health effects from lead. Other governance instruments mention children's unique vulnerability to ozone, particulate matter and carbon monoxide, but do not provide further details. Most interviewees were aware of Mexican environmental policy tools addressing children's health needs, but agreed that, with few exceptions, environmental policies do not address the specific health needs of children and pregnant women. Interviewees also cited state centralization of power, communication barriers and political resistance as reasons for the absence of a strong regulatory platform. The Mexican government has not sufficiently accounted for children's unique vulnerability to environmental contaminants. If regulation and legislation are not updated and implemented to protect children, increases in preventable exposures to toxic chemicals in the environment may ensue.


Development of an effective sample transfer device for biomarker detection in nasal secretions.
Nasal secretions (NS) reflect inflammatory activity of the nasal mucosa and thus can be utilized for disease diagnosis and determining treatment effects in Allergic rhinitis (AR). However, non-standardized collection of samples can affect the measured concentration of inflammatory biomarker in NS. In this study, we aimed to develop and evaluate new devices capable of standardizing the collection, storage, and preprocessing methods of NS samples. First, we chose the best swab as polyester (PE) and selected a stimulation method, twirling for 10 s at 1 Hz, to efficiently release AR biomarkers from a PE swab. Storage of sample solutions at -20 °C was optimal for the stability of biomarkers for the detection of AR. The new swab sample transfer device showed excellent concentration recovery efficiency (90-100%) for tryptase (Trp) and eosinophil cationic protein (ECP) without crosstalk between the two biomarkers. Finally, we compared the concentration of Trp in human NS samples of AR patients (n = 6) pre-processed by the new device with that by centrifuge as a standard method. As a result, the concentrations of Trp in NS were very similar in both groups. Therefore, this device can be utilized as an effective sample transfer and pre-processing device for point-of-care testing of AR.


Morphology, molecular phylogeny and azaspiracid profile of Azadinium poporum (Dinophyceae) from the Gulf of Mexico.
Azadinium poporum produces a variety of azaspiracids and consists of several ribotypes, but information on its biogeography is limited. A strain of A. poporum (GM29) was incubated from a Gulf of Mexico sediment sample. Strain GM29 was characterized by a plate pattern of po, cp, x, 4', 3a, 6″, 6C, 5S, 6‴, 2⁗, a distinct ventral pore at the junction of po and the first two apical plates, and a lack of an antapical spine, thus fitting the original description of A. poporum. The genus Azadinium has not been reported in waters of the United States of America before this study. Molecular phylogeny, based on large subunit ribosomal DNA (LSU rDNA) and internal transcribed spacer (ITS) sequences, reveals that strain GM29 is nested within the well-resolved A. poporum complex, but forms a sister clade either to ribotype B (ITS) or ribotype C (LSU). It is, therefore, designated as a new ribotype, termed as ribotype D. LSU and ITS sequences similarity among different ribotypes of A. poporum ranges from 95.4% to 98.2%, and from 97.1% to 99.2% respectively, suggesting that the LSU fragment is a better candidate for molecular discrimination. Azaspiracid profiles were analyzed using LC-MS/MS and demonstrate that strain GM29 produces predominantly AZA-2 with an amount of 45fg/cell. The results suggest that A. poporum has a wide distribution and highlights the risk potential of azaspiracid intoxication in the United States.


Using community advisory boards to reduce environmental barriers to health in American Indian communities, Wisconsin, 2007-2012.
American Indian communities have a high prevalence of chronic diseases including diabetes, obesity, cardiovascular disease, and cancer. Innovative community-based approaches are needed to identify, prioritize, and create sustainable interventions to reduce environmental barriers to healthy lifestyles and ultimately improve health. Healthy Children, Strong Families was a family-based and community-based intervention to increase healthy lifestyles on Wisconsin American Indian reservations. This intervention arose from a long-standing partnership between University of Wisconsin researchers and 3 of these American Indian communities. In each community, community advisory boards (CABs) were established by the residents and university partners. CAB meetings were open and held at various times and locations to increase member participation. CABs featured continual, snowball recruitment; internal and external expert consultation; and coordination with standing tribal committees. Meetings initially focused on understanding community supports for and barriers to healthy lifestyles but quickly turned toward community action for change. CAB interventions decreased environmental barriers to health at each site and improved options for healthy lifestyle choices. Over 5 years, 71 CAB meetings occurred with a total of 1,070 participants. Successful CAB interventions included planting community gardens and an apple orchard, conducting gardening and canning workshops, instituting food-related policies and dog control regulations, building an environmentally friendly playground, and providing access to recreational facilities. The CABs are now self-sustaining. CABs can be highly effective action teams capable of improving community environments. Our experience shows that academic researchers can partner with community residents to generate programs and policies that will expand access to local food, increase people's choices for engaging in physical activity, and encourage local policy changes that improve overall community health.


Course of Early Neurologic Symptom Severity after Endovascular Treatment of Anterior Circulation Large Vessel Occlusion Stroke: Association with Baseline Multiparametric CT Imaging and Clinical Parameters.
Neurologic symptom severity and deterioration at 24 hours (h) predict long-term outcomes in patients with acute large vessel occlusion (LVO) stroke of the anterior circulation. We aimed to examine the association of baseline multiparametric CT imaging and clinical factors with the course of neurologic symptom severity in the first 24 h after endovascular treatment (EVT). Patients with LVO stroke of the anterior circulation were selected from a prospectively acquired consecutive cohort of patients who underwent multiparametric CT, including non-contrast CT, CT angiography and CT perfusion before EVT. The symptom severity was assessed on admission and after 24 h using the 42-point National Institutes of Health Stroke Scale (NIHSS). Clinical and imaging data were compared between patients with and without early neurological deterioration (END). END was defined as an increase in ≥4 points, and a significant clinical improvement as a decrease in ≥4 points, compared to NIHSS on admission. Multivariate regression analyses were used to determine independent associations of imaging and clinical parameters with NIHSS score increase or decrease in the first 24 h. A total of 211 patients were included, of whom 38 (18.0%) had an END. END was significantly associated with occlusion of the internal carotid artery (odds ratio (OR), 4.25; 95% CI, 1.90-9.47) and the carotid T (OR, 6.34; 95% CI, 2.56-15.71), clot burden score (OR, 0.79; 95% CI, 0.68-0.92) and total ischemic volume (OR, 1.01; 95% CI, 1.00-1.01). In a comprehensive multivariate analysis model including periprocedural parameters and complications after EVT, carotid T occlusion remained independently associated with END, next to reperfusion status and intracranial hemorrhage. Favorable reperfusion status and small ischemic core volume were associated with clinical improvement after 24 h. The use of imaging parameters as a surrogate for early NIHSS progression in an acute LVO stroke after EVT reached limited performance with only carotid T occlusion as an independent predictor of END. Reperfusion status and early complications in terms of intracranial hemorrhage are critical factors that influence patient outcome in the acute stroke phase after EVT.


Sarcopenia in daily practice: assessment and management.
Sarcopenia is increasingly recognized as a correlate of ageing and is associated with increased likelihood of adverse outcomes including falls, fractures, frailty and mortality. Several tools have been recommended to assess muscle mass, muscle strength and physical performance in clinical trials. Whilst these tools have proven to be accurate and reliable in investigational settings, many are not easily applied to daily practice. This paper is based on literature reviews performed by members of the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO) working group on frailty and sarcopenia. Face-to-face meetings were afterwards organized for the whole group to make amendments and discuss further recommendations. This paper proposes some user-friendly and inexpensive methods that can be used to assess sarcopenia in real-life settings. Healthcare providers, particularly in primary care, should consider an assessment of sarcopenia in individuals at increased risk; suggested tools for assessing risk include the Red Flag Method, the SARC-F questionnaire, the SMI method or different prediction equations. Management of sarcopenia should primarily be patient centered and involve the combination of both resistance and endurance based activity programmes with or without dietary interventions. Development of a number of pharmacological interventions is also in progress. Assessment of sarcopenia in individuals with risk factors, symptoms and/or conditions exposing them to the risk of disability will become particularly important in the near future.


Force-free swimming of a model helical flagellum in viscoelastic fluids.
We precisely measure the force-free swimming speed of a rotating helix in viscous and viscoelastic fluids. The fluids are highly viscous to replicate the low Reynolds number environment of microorganisms. The helix, a macroscopic scale model for the bacterial flagellar filament, is rigid and rotated at a constant rate while simultaneously translated along its axis. By adjusting the translation speed to make the net hydrodynamic force vanish, we measure the force-free swimming speed as a function of helix rotation rate, helix geometry, and fluid properties. We compare our measurements of the force-free swimming speed of a helix in a high-molecular weight silicone oil with predictions for the swimming speed in a Newtonian fluid, calculated using slender-body theories and a boundary-element method. The excellent agreement between theory and experiment in the Newtonian case verifies the high accuracy of our experiments. For the viscoelastic fluid, we use a polymer solution of polyisobutylene dissolved in polybutene. This solution is a Boger fluid, a viscoselastic fluid with a shear-rate-independent viscosity. The elasticity is dominated by a single relaxation time. When the relaxation time is short compared to the rotation period, the viscoelastic swimming speed is close to the viscous swimming speed. As the relaxation time increases, the viscoelastic swimming speed increases relative to the viscous speed, reaching a peak when the relaxation time is comparable to the rotation period. As the relaxation time is further increased, the viscoelastic swimming speed decreases and eventually falls below the viscous swimming speed.


NADPH oxidase contributes to streptozotocin-induced neurodegeneration.
Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the progressive loss of memory. The neurodegeneration induced by AD has been linked to oxidative damage. However, little is known about the involvement of NADPH oxidase 2 (Nox2), a multisubunit enzyme that catalyzes the reduction of oxygen to produce reactive oxygen species, in the pathogenesis of AD. The main purpose of this study was to investigate the involvement of Nox2 in memory, in AD-related brain abnormalities, oxidative damage, inflammation and neuronal death in the hippocampus in the streptozotocin (STZ)-induced AD-like state by comparing the effects of that drug on mice lacking gp91phox-/- and wild-type (Wt) mice. Nox2 gene expression was found increased in Wt mice after STZ injection. In object recognition test, Wt mice injected with STZ presented impairment in short- and long-term memory, which was not observed following Nox2 deletion. STZ treatment induced increased phosphorylation of Tau and increased amyloid-β, apoptosis-inducing factor (AIF) and astrocyte and microglial markers expression in Wt mice but not in gp91phox-/-. STZ treatment increased oxidative damage and pro-inflammatory cytokines' release in Wt mice, which was not observed in gp91phox-/- mice. Nox2 deletion had a positive effect on the IL-10 baseline production, suggesting that this cytokine might contribute to the neuroprotection mechanism against STZ-induced neurodegeneration. In summary, our data suggest that the Nox2-dependent reactive oxygen species (ROS) generation contributes to the STZ-induced AD-like state.


Language ability predicts the development of behavior problems in children.
Prior studies have suggested, but not fully established, that language ability is important for regulating attention and behavior. Language ability may have implications for understanding attention-deficit hyperactivity disorder (ADHD) and conduct disorders, as well as subclinical problems. This article reports findings from two longitudinal studies to test (a) whether language ability has an independent effect on behavior problems, and (b) the direction of effect between language ability and behavior problems. In Study 1 (N = 585), language ability was measured annually from ages 7 to 13 years by language subtests of standardized academic achievement tests administered at the children's schools. Inattentive-hyperactive (I-H) and externalizing (EXT) problems were reported annually by teachers and mothers. In Study 2 (N = 11,506), language ability (receptive vocabulary) and mother-rated I-H and EXT problems were measured biannually from ages 4 to 12 years. Analyses in both studies showed that language ability predicted within-individual variability in the development of I-H and EXT problems over and above the effects of sex, ethnicity, socioeconomic status (SES), and performance in other academic and intellectual domains (e.g., math, reading comprehension, reading recognition, and short-term memory [STM]). Even after controls for prior levels of behavior problems, language ability predicted later behavior problems more strongly than behavior problems predicted later language ability, suggesting that the direction of effect may be from language ability to behavior problems. The findings suggest that language ability may be a useful target for the prevention or even treatment of attention deficits and EXT problems in children.


The effect of etanercept on traditional metabolic risk factors for cardiovascular disease in patients with rheumatoid arthritis.
Patients with rheumatoid arthritis (RA) are at an increased risk of cardiovascular disease (CVD). Treatment with tumor necrosis factor inhibitors improves both joint symptoms associated with RA and also CVD risk. This exploratory analysis of a phase 4 study evaluated changes in metabolic risk factors in patients with RA treated with etanercept. Metabolic analytes were measured at baseline, week 12, and week 24 in patients enrolled in a randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of etanercept in moderately active RA. Patients received either placebo or etanercept 50 mg every week (QW) for 12 weeks, after which all patients received etanercept 50 mg QW through week 24. Levels of metabolic analytes were assessed in all patients, including patients with diabetes and hyperlipidemia, and described descriptively. A total of 210 patients were randomized, 104 to placebo and 106 to etanercept. There were no significant changes in metabolic risk factors from baseline to week 12 or 24 in all patients. Levels of metabolic analytes were similar in patients with diabetes and hyperlipidemia, with some exceptions; fasting glucose and fasting insulin decreased through week 12, and hemoglobin A1C decreased slightly through week 24 in patients with diabetes. Treatment with etanercept did not adversely affect levels of metabolic risk factors for CVD in patients with RA.


Hepatotoxicity associated with weight loss or sports dietary supplements, including OxyELITE Pro™ - United States, 2013.
In September 2013, the Hawaii Department of Health (HDOH) was notified of seven adults who developed acute hepatitis after taking OxyELITE Pro™, a weight loss and sports dietary supplement. CDC assisted HDOH with their investigation, then conducted case-finding outside of Hawaii with FDA and the Department of Defense (DoD). We defined cases as acute hepatitis of unknown etiology that occurred from April 1, 2013, through December 5, 2013, following exposure to a weight loss or muscle-building dietary supplement, such as OxyELITE Pro™. We conducted case-finding through multiple sources, including data from poison centers (National Poison Data System [NPDS]) and FDA MedWatch. We identified 40 case-patients in 23 states and two military bases with acute hepatitis of unknown etiology and exposure to a weight loss or muscle building dietary supplement. Of 35 case-patients who reported their race, 15 (42.9%) reported white and 9 (25.7%) reported Asian. Commonly reported symptoms included jaundice, fatigue, and dark urine. Twenty-five (62.5%) case-patients reported taking OxyELITE Pro™. Of these 25 patients, 17 of 22 (77.3%) with available data were hospitalized and 1 received a liver transplant. NPDS and FDA MedWatch each captured seven (17.5%) case-patients. Improving the ability to search surveillance systems like NPDS and FDA MedWatch for individual and grouped dietary supplements, as well as coordinating case-finding with DoD, may benefit ongoing surveillance efforts and future outbreak responses involving adverse health effects from dietary supplements. This investigation highlights opportunities and challenges in using multiple sources to identify cases of suspected supplement associated adverse events. Published 2016. This article is a U.S. Government work and is in the public domain in the USA.


BCL9/9L-β-catenin Signaling is Associated With Poor Outcome in Colorectal Cancer.
BCL9/9L proteins enhance the transcriptional output of the β-catenin/TCF transcriptional complex and contribute critically to upholding the high WNT signaling level required for stemness maintenance in the intestinal epithelium. Here we show that a BCL9/9L-dependent gene signature derived from independent mouse colorectal cancer (CRC) models unprecedentedly separates patient subgroups with regard to progression free and overall survival. We found that this effect was by and large attributable to stemness related gene sets. Remarkably, this signature proved associated with recently described poor prognosis CRC subtypes exhibiting high stemness and/or epithelial-to-mesenchymal transition (EMT) traits. Consistent with the notion that high WNT signaling is required for stemness maintenance, ablating Bcl9/9l-β-catenin in murine oncogenic intestinal organoids provoked their differentiation and completely abrogated their tumorigenicity, while not affecting their proliferation. Therapeutic strategies aimed at targeting WNT responses may be limited by intestinal toxicity. Our findings suggest that attenuating WNT signaling to an extent that affects stemness maintenance without disturbing intestinal renewal might be well tolerated and prove sufficient to reduce CRC recurrence and dramatically improve disease outcome.


The use of the harmonic scalpel versus knot tying for modified radical neck dissection.
Although the utility of the harmonic scalpel (HS) in thyroidectomy has been extensively demonstrated, there is little experience regarding its use for neck dissections. Within 10 years, 119 patients underwent modified radical neck dissection (MRND) for thyroid cancer. In 51 patients, MRND was performed using conventional knot tying and in 68 using the HS. The number of lymph nodes (LNs) removed, operative time, estimated blood loss (EBL), drain output, duration of the drainage, and complications were compared for 47 patients undergoing first-time unilateral MRND without concomitant additional surgical procedures. The number of LNs removed, operative time, duration of drainage, and rate of lymphatic leak were similar between groups. For the HS group, EBL (5 ± 3 vs 32 ± 10; P = .006) and drain output on postoperative day 1 (51.7 ± 6.2 vs 78.9 ± 11.9; P = .02) and at 1 week (6.1 ± 1.2 vs 10.2 ± 1.8, respectively; P = .03) were significantly less. Despite the limitations of its retrospective nature, this study shows that the HS reduces EBL and the amount of lymphatic drainage compared to knot tying after MRND.


Facial-expression and gaze-selective responses in the monkey amygdala.
The social behavior of both human and nonhuman primates relies on specializations for the recognition of individuals, their facial expressions, and their direction of gaze. A broad network of cortical and subcortical structures has been implicated in face processing, yet it is unclear whether co-occurring dimensions of face stimuli, such as expression and direction of gaze, are processed jointly or independently by anatomically and functionally segregated neural structures. Awake macaques were presented with a set of monkey faces displaying aggressive, neutral, and appeasing expressions with head and eyes either averted or directed. BOLD responses to these faces as compared to Fourier-phase-scrambled images revealed widespread activation of the superior temporal sulcus and inferotemporal cortex and included activity in the amygdala. The different dimensions of the face stimuli elicited distinct activation patterns among the amygdaloid nuclei. The basolateral amygdala, including the lateral, basal, and accessory basal nuclei, produced a stronger response for threatening than appeasing expressions. The central nucleus and bed nucleus of the stria terminalis responded more to averted than directed-gaze faces. Independent behavioral measures confirmed that faces with averted gaze were more arousing, suggesting the activity in the central nucleus may be related to attention and arousal.


Demonstration of a cavity coupler based on a resonant waveguide grating.
Thermal noise in multilayer optical coatings may not only limit the sensitivity of future gravitational wave detectors in their most sensitive frequency band but is also a major impediment for experiments that aim to reach the standard quantum limit or to cool mechanical systems to their quantum ground state. Here, we present the experimental realization and characterization of a cavity coupler, which is based on a surface relief guided ode resonant grating. Since the required thickness of the dielectric coating is dramatically decreased compared to conventional mirrors, it is expected to provide low mechanical loss and, thus, low thermal noise. The cavity coupler was incorporated into a Fabry-Perot resonator together with a conventional high quality mirror. The finesse of this cavity was measured to be F = 657, which corresponds to a coupler reflectivity of R = 99.08 %.


Transgenerational effects of caloric restriction on appetite: a meta-analysis.
Maternal undernutrition can result in significant alterations to the post-natal offspring phenotype, including body size and behaviour. For example, maternal food restriction has been implicated in offspring hyperphagia, potentially causing increased weight gain and fat accumulation. This could result in obesity and other adverse long-term health effects in offspring. We investigated the link between maternal caloric restriction during gestation and offspring appetite by conducting the first meta-analysis on this topic using experimental data from mammalian laboratory models (i.e. rats and mice). We collected 89 effect sizes from 35 studies, together with relevant moderators. Our analysis revealed weak and statistically non-significant overall effect on offspring's appetite. However, we found that lower protein content of restricted diets is associated with higher food intake in female offspring. Importantly, we show that a main source of variation among studies arises from whether, and how, food intake was adjusted for body mass. This probably explains many of the contradictory results in the field. Based on our results, we recommend using allometric scaling of food intake to body mass in future studies.


Adaptation of object descriptions to a partner under increasing communicative demands: a comparison of children with and without autism.
This study compared the object descriptions of school-age children with high-functioning autism (HFA) with those of a matched group of typically developing children. Descriptions were elicited in a referential communication task where shared information was manipulated, and in a guessing game where clues had to be provided about the identity of an object that was hidden from the addressee. Across these tasks, increasingly complex levels of audience design were assessed: (1) the ability to give adequate descriptions from one's own perspective, (2) the ability to adjust descriptions to an addressee's perspective when this differs from one's own, and (3) the ability to provide indirect yet identifying descriptions in a situation where explicit labeling is inappropriate. Results showed that there were group differences in all three cases, with the HFA group giving less efficient descriptions with respect to the relevant context than the comparison group. More revealing was the identification of distinct adaptation profiles among the HFA participants: those who had difficulty with all three levels, those who displayed Level 1 audience design but poor Level 2 and Level 3 design, and those demonstrated all three levels of audience design, like the majority of the comparison group. Higher structural language ability, rather than symptom severity or social skills, differentiated those HFA participants with typical adaptation profiles from those who displayed deficient audience design, consistent with previous reports of language use in autism.


Wellen's syndrome: An ominous EKG pattern.
Wellen's syndrome is a characteristic T-wave on an electrocardiogram during a pain-free period in a patient with intermittent chest pain. This finding suggests a high-degree stenosis of the proximal left anterior descending (LAD) coronary artery that will soon result in an acute anterior wall myocardial infarction (MI) if the patient is not urgently catheterized and the occlusion opened. This case report discusses a young male patient with no known cardiac disease with an EKG that demonstrates the classic Wellen's T-waves. He was urgently taken to cardiac catheterization and his 95% proximal LAD stenosis was reduced via drug-eluding stent. Through knowledge of Wellen's T-waves, more anterior wall MIs can be prevented.


Satisfaction with care: do Medicare HMOs make a difference?
Differences in satisfaction with care and perceptions of doctor/patient interactions were compared for Medicare beneficiaries enrolled in health maintenance organizations (HMOs) and beneficiaries in the fee-for-service (FFS) sector (nonenrollees). After controlling for covariates, beneficiaries expressed satisfaction with their care, regardless of where they received it. However, HMO enrollees were more likely than nonenrollees were to be very satisfied with the costs of care and with getting care at one location. In contrast, for every components-of-care measure, nonenrollees were more likely than HMO enrollees were to indicate high satisfaction with the quality of interaction with their physicians.


Identification and Characterization of Post-activated B Cells in Systemic Autoimmune Diseases.
Autoimmune diseases (AID) such as systemic lupus erythematosus (SLE), primary Sjögren's syndrome (pSS), and rheumatoid arthritis (RA) are chronic inflammatory diseases in which abnormalities of B cell function play a central role. Although it is widely accepted that autoimmune B cells are hyperactive in vivo, a full understanding of their functional status in AID has not been delineated. Here, we present a detailed analysis of the functional capabilities of AID B cells and dissect the mechanisms underlying altered B cell function. Upon BCR activation, decreased spleen tyrosine kinase (Syk) and Bruton's tyrosine kinase (Btk) phosphorylation was noted in AID memory B cells combined with constitutive co-localization of CD22 and protein tyrosine phosphatase (PTP) non-receptor type 6 (SHP-1) along with hyporesponsiveness to TLR9 signaling, a Syk-dependent response. Similar BCR hyporesponsiveness was also noted specifically in SLE CD27- B cells together with increased PTP activities and increased transcripts for PTPN2, PTPN11, PTPN22, PTPRC, and PTPRO in SLE B cells. Additional studies revealed that repetitive BCR stimulation of normal B cells can induce BCR hyporesponsiveness and that tissue-resident memory B cells from AID patients also exhibited decreased responsiveness immediately ex vivo, suggesting that the hyporesponsive status can be acquired by repeated exposure to autoantigen(s) in vivo. Functional studies to overcome B cell hyporesponsiveness revealed that CD40 co-stimulation increased BCR signaling, induced proliferation, and downregulated PTP expression (PTPN2, PTPN22, and receptor-type PTPs). The data support the conclusion that hyporesponsiveness of AID and especially SLE B cells results from chronic in vivo stimulation through the BCR without T cell help mediated by CD40-CD154 interaction and is manifested by decreased phosphorylation of BCR-related proximal signaling molecules and increased PTPs. The hyporesponsiveness of AID B cells is similar to a form of functional anergy.


Desflurane and Surgery Exposure During Pregnancy Decrease Synaptic Integrity and Induce Functional Deficits in Juvenile Offspring Mice.
Anesthesia in pregnant women may cause adverse effects in the hippocampus of unborn babies and fetal brain development. The mechanisms underlying pathological changes resulting from anesthetics are unclear. This study tested the hypothesis that exposure to desflurane during pregnancy may impair cognition and memory functions of juvenile offspring. Pregnant mice (at gestational day 14) were administered 10% desflurane for 3 h and compared to sham control and sciatic nerve hemi-transection surgery. Hippocampal tissues of both fetal (G14) and offspring mice (postnatal day 31) were collected and analyzed by real-time qPCR and Western blot. Functional tests were performed to assess fear and memory functions in offspring mice. Primary hippocampal neuronal cultures from postnatal day 0 (without desflurane exposure) were examined for neuronal and synaptic development under desflurane treatment in vitro. In this acute experiment, we showed that neuronal cultures exposed to desflurane significantly increased interleukin (IL)-6 expression and apoptotic gene caspase-3 activation. Desflurane exposure significantly reduced PSD-95 expression in hippocampal neurons. Similar changes were observed in hippocampal tissues from juvenile offspring mice. Inhaled desflurane impaired memory functions in offspring mice compared to sham control. These mice displayed higher sensitivity to fear conditioning. Neurons isolated from the mice exposed to desflurane exhibited significantly lower levels of synaptophysin expression. These results suggest that anesthetic exposure together with surgery during pregnancy may induce detrimental effects in juvenile offspring mice via the induction of cell death and disruption of synaptic integrity.


Infantile Colic-The Perspective of German and Polish Pediatricians in 2020.
The objective of the study was to characterize how infantile colic is perceived and managed by German and Polish pediatricians. Data in both countries were collected by using a paper questionnaire with seven questions and predefined and free text fields for the answers. Answers from 160 German and 133 Polish pediatricians were collected. The average of the occurrence rates estimated by both responder groups were at the higher end of published rates. The majority of pediatricians from both countries rated the parental burden caused by infantile colic to be high or very high. Pediatricians' awareness about the association between infantile colic and maternal depression and premature termination of breastfeeding is relatively well established in both countries. While more than 90% of German pediatricians stated knowledge of infantile colic being a major risk factor for shaken baby syndrome, this knowledge was only declared by half of the Polish responders. Pharmacological interventions, pro-/synbiotics or simethicone, are part of the treatment repertoire of nearly all responding pediatricians. In addition, non-pharmacological interventions (e.g., change of feeding, change of parental behavior) are also among the employed interventions. Results of this study will allow to better design and prioritize communication about infantile colic directed at pediatricians.


How ecologists define drought, and why we should do better.
Drought, widely studied as an important driver of ecosystem dynamics, is predicted to increase in frequency and severity globally. To study drought, ecologists must define or at least operationalize what constitutes a drought. How this is accomplished in practice is unclear, particularly given that climatologists have long struggled to agree on definitions of drought, beyond general variants of "an abnormal deficiency of water." We conducted a literature review of ecological drought studies (564 papers) to assess how ecologists describe and study drought. We found that ecologists characterize drought in a wide variety of ways (reduced precipitation, low soil moisture, reduced streamflow, etc.), but relatively few publications (~32%) explicitly define what are, and are not, drought conditions. More troubling, a surprising number of papers (~30%) simply equated "dry conditions" with "drought" and provided little characterization of the drought conditions studied. For a subset of these, we calculated Standardized Precipitation Evapotranspiration Index values for the reported drought periods. We found that while almost 90% of the studies were conducted under conditions quantifiable as slightly to extremely drier than average, ~50% were within the range of normal climatic variability. We conclude that the current state of the ecological drought literature hinders synthesis and our ability to draw broad ecological inferences because drought is often declared but is not explicitly defined or well characterized. We suggest that future drought publications provide at least one of the following: (a) the climatic context of the drought period based on long-term records; (b) standardized climatic index values; (c) published metrics from drought-monitoring organizations; (d) a quantitative definition of what the authors consider to be drought conditions for their system. With more detailed and consistent quantification of drought conditions, comparisons among studies can be more rigorous, increasing our understanding of the ecological effects of drought.


Transcatheter aortic valve implantation vs. surgical aortic valve replacement for treatment of symptomatic severe aortic stenosis: an updated meta-analysis.
Owing to new evidence from randomized controlled trials (RCTs) in low-risk patients with severe aortic stenosis, we compared the collective safety and efficacy of transcatheter aortic valve implantation (TAVI) vs. surgical aortic valve replacement (SAVR) across the entire spectrum of surgical risk patients. The meta-analysis is registered with PROSPERO (CRD42016037273). We identified RCTs comparing TAVI with SAVR in patients with severe aortic stenosis reporting at different follow-up periods. We extracted trial, patient, intervention, and outcome characteristics following predefined criteria. The primary outcome was all-cause mortality up to 2 years for the main analysis. Seven trials that randomly assigned 8020 participants to TAVI (4014 patients) and SAVR (4006 patients) were included. The combined mean STS score in the TAVI arm was 9.4%, 5.1%, and 2.0% for high-, intermediate-, and low surgical risk trials, respectively. Transcatheter aortic valve implantation was associated with a significant reduction of all-cause mortality compared to SAVR {hazard ratio [HR] 0.88 [95% confidence interval (CI) 0.78-0.99], P = 0.030}; an effect that was consistent across the entire spectrum of surgical risk (P-for-interaction = 0.410) and irrespective of type of transcatheter heart valve (THV) system (P-for-interaction = 0.674). Transcatheter aortic valve implantation resulted in lower risk of strokes [HR 0.81 (95% CI 0.68-0.98), P = 0.028]. Surgical aortic valve replacement was associated with a lower risk of major vascular complications [HR 1.99 (95% CI 1.34-2.93), P = 0.001] and permanent pacemaker implantations [HR 2.27 (95% CI 1.47-3.64), P < 0.001] compared to TAVI. Compared with SAVR, TAVI is associated with reduction in all-cause mortality and stroke up to 2 years irrespective of baseline surgical risk and type of THV system.


Lifetime of Ionic Vacancy Created in Redox Electrode Reaction Measured by Cyclotron MHD Electrode.
The lifetimes of ionic vacancies created in ferricyanide-ferrocyanide redox reaction have been first measured by means of cyclotron magnetohydrodynamic electrode, which is composed of coaxial cylinders partly exposed as electrodes and placed vertically in an electrolytic solution under a vertical magnetic field, so that induced Lorentz force makes ionic vacancies circulate together with the solution along the circumferences. At low magnetic fields, due to low velocities, ionic vacancies once created become extinct on the way of returning, whereas at high magnetic fields, in enhanced velocities, they can come back to their initial birthplaces. Detecting the difference between these two states, we can measure the lifetime of ionic vacancy. As a result, the lifetimes of ionic vacancies created in the oxidation and reduction are the same, and the intrinsic lifetime is 1.25 s, and the formation time of nanobubble from the collision of ionic vacancies is 6.5 ms.


Zone plate method for electronic holographic display using resolution redistribution technique.
The resolution redistribution (RR) technique can increase the horizontal viewing-zone angle and screen size of electronic holographic display. The present study developed a zone plate method that would reduce hologram calculation time for the RR technique. This method enables calculation of an image displayed on a spatial light modulator by performing additions of the zone plates, while the previous calculation method required performing the Fourier transform twice. The derivation and modeling of the zone plate are shown. In addition, the look-up table approach was introduced for further reduction in computation time. Experimental verification using a holographic display module based on the RR technique is presented.


Crystal structure of the C2 fragment of streptococcal protein G in complex with the Fc domain of human IgG.
Streptococcal protein G comprises two or three domains that bind to the constant Fc region of most mammalian immunoglobulin Gs (IgGs). Protein G is functionally related to staphylococcal protein A, with which it shares neither sequence nor structural homology. To understand the competitive binding of these two proteins to the Fc region, the crystal structure of a single Ig-binding domain of streptococcal protein G was determined at 3.5 A resolution in complex with the Fc fragment of human IgG and compared with the structures of protein A:Fc and protein G:Fab complexes. Protein G binds to the interface between the second and third heavy chain constant domains of Fc, which is roughly the same binding site used by protein A. Protein G comprises one alpha-helix packed onto a four-stranded beta-sheet. Residues from protein G that are involved in binding are situated within the C-terminal part of the alpha-helix, the N-terminal part of the third beta-strand and the loop region connecting these two structural elements. The identified Fc-binding region of protein G agrees well with both biochemical and NMR spectroscopic data. However, the Fc-binding helices of protein G and protein A are not superimposable. Protein G and protein A have developed different strategies for binding to Fc. The protein G:Fc complex involves mainly charged and polar contacts, whereas protein A and Fc are held together through non-specific hydrophobic interactions and a few polar interactions. Several residues of Fc are involved in both the protein G:Fc and the protein A:Fc interaction, which explains the competitive binding of the two proteins. The apparent differences in their Fc-binding activities result from additional unique interactions.


Effect of Zingiber officinale R. rhizomes (ginger) on pain relief in primary dysmenorrhea: a placebo randomized trial.
Zingiber officinale R. rhizome (ginger) is a popular spice that has traditionally been used to combat the effects of various inflammatory diseases. The aim of this study was to evaluate the effects of ginger on pain relief in primary dysmenorrhea. This was a randomized, controlled trial. The study was based on a sample of one hundred and twenty students with moderate or severe primary dysmenorrhea. The students were all residents of the dormitories of Shahed University. They were randomly assigned into two equal groups, one for ginger and the other for placebo in two different treatment protocols with monthly intervals. The ginger and placebo groups in both protocols received 500 mg capsules of ginger root powder or placebo three times a day. In the first protocol ginger and placebo were given two days before the onset of the menstrual period and continued through the first three days of the menstrual period. In the second protocol ginger and placebo were given only for the first three days of the menstrual period. Severity of pain was determined by a verbal multidimensional scoring system and a visual analogue scale. There was no difference in the baseline characteristics of the two groups (placebo n = 46, ginger n = 56). The results of this study showed that there were significant differences in the severity of pain between ginger and placebo groups for protocol one (P = 0.015) and protocol two (P = 0.029). There was also significant difference in duration of pain between the two groups for protocol one (P = 0.017) but not for protocol two (P = 0.210). Treatment of primary dysmenorrhea in students with ginger for 5 days had a statistically significant effect on relieving intensity and duration of pain. IRCT201105266206N3.


Face emotion recognition is related to individual differences in psychosis-proneness.
Deficits in face emotion recognition (FER) in schizophrenia are well documented, and have been proposed as a potential intermediate phenotype for schizophrenia liability. However, research on the relationship between psychosis vulnerability and FER has mixed findings and methodological limitations. Moreover, no study has yet characterized the relationship between FER ability and level of psychosis-proneness. If FER ability varies continuously with psychosis-proneness, this suggests a relationship between FER and polygenic risk factors. We tested two large internet samples to see whether psychometric psychosis-proneness, as measured by the Schizotypal Personality Questionnaire-Brief (SPQ-B), is related to differences in face emotion identification and discrimination or other face processing abilities. Experiment 1 (n=2332) showed that psychosis-proneness predicts face emotion identification ability but not face gender identification ability. Experiment 2 (n=1514) demonstrated that psychosis-proneness also predicts performance on face emotion but not face identity discrimination. The tasks in Experiment 2 used identical stimuli and task parameters, differing only in emotion/identity judgment. Notably, the relationships demonstrated in Experiments 1 and 2 persisted even when individuals with the highest psychosis-proneness levels (the putative high-risk group) were excluded from analysis. Our data suggest that FER ability is related to individual differences in psychosis-like characteristics in the normal population, and that these differences cannot be accounted for by differences in face processing and/or visual perception. Our results suggest that FER may provide a useful candidate intermediate phenotype.


New devices in heart failure: an European Heart Rhythm Association report: developed by the European Heart Rhythm Association; endorsed by the Heart Failure Association.
Several new devices for the treatment of heart failure (HF) patients have been introduced and are increasingly used in clinical practice or are under clinical evaluation in either observational and/or randomized clinical trials. These devices include cardiac contractility modulation, spinal cord stimulation, carotid sinus nerve stimulation, cervical vagal stimulation, intracardiac atrioventricular nodal vagal stimulation, and implantable hemodynamic monitoring devices. This task force believes that an overview on these technologies is important. Special focus is given to patients with HF New York Heart Association Classes III and IV and narrow QRS complex, who represent the largest group in HF compared with patients with wide QRS complex. An overview on potential device options in addition to optimal medical therapy will be helpful for all physicians treating HF patients.


Fluid transport: concentration of the intercellular compartment.
Intercellular spaces of Periplaneta rectal pads are visible at a magnification of x 100 and distend during fluid uptake. Samples (0.025 to 0.1 nanoliter) obtained by micropuncture from the spaces were consistently more concentrated than the fluid in the rectal lumen. This observation supports the hypothesis of "local" osmosis in epithelial fluid transport.


The thermal and storage stability of bovine haemoglobin by ultraviolet-visible and circular dichroism spectroscopies.
The effects of temperature, pH and long-term storage on the secondary structure and conformation changes of bovine haemoglobin (bHb) were studied using circular dichroism (CD) and ultraviolet--visible (UV-vis) spectroscopies. Neural network software was used to deconvolute the CD data to obtain the fractional content of the five secondary structures. The storage stability of bHb solutions in pH 6, 7 and 8 buffers was significantly higher at 4 °C than at 23 °C for the first 3 days. A complete denaturation of bHb was observed after 40 days irrespective of storage temperature or pH. The bHb solutions were also exposed to heating and cooling cycles between 25 and 65 °C and structural changes were followed by UV-vis and CD spectroscopies. These experiments demonstrated that α-helix content of bHb decreased steadily with the increasing temperature above 35 °C at all pH values. The loss in α-helicity and gain in random coil conformations was pH-dependent and the greatest under alkaline conditions. Furthermore, there was minimal recovery of the secondary structure content upon cooling to 25 °C. The use of bHb as a model drug is very common and this study elucidates the significance of storage and processing conditions on its stability.


Technologic advances for evaluation of cervical cytology: is newer better?
Among those women who have cervical cancer and have been screened, 14% to 33% of the cases represent failure to detect abnormalities that existed at the time of screening. New technologies intended to improve detection of cytologic abnormalities include liquid-based, thin-layer cytology (ThinPrep, AutoCyte), computerized rescreening (PAPNET), and algorithm-based computer rescreening (AutoPap). This report combines evidence reviews conducted for the U.S. Preventive Services Task Force and the Agency for Healthcare Research and Quality, in which we systematically identified articles on cervical neoplasia, cervical dysplasia, and screening published between January 1966 and March 2001. We note the challenges for improving screening methods, providing an overview of methods for collecting and evaluating cytologic samples, and examining the evidence about the diagnostic performance of new technologies for detecting cervical lesions. Using standard criteria for evaluation of the diagnostic tests, we determined that knowledge about the sensitivity, specificity, and predictive values of new technologies is meager. Only one study of liquid-based cytology used a reference standard of colposcopy, with histology as indicated, to assess participants with normal screening results. Lack of an adequate reference standard is the overwhelming reason that test characteristics cannot be properly assessed or compared. Most publications compare results of screening using the new technology with expert panel review of the cytologic specimen. In that case, the tests are not independent measures and do nothing to relate the screening test findings to the true status of the cervix, making determination of false-negatives, and thus sensitivity, specificity, and negative predictive value, impossible. We did not identify any literature about health outcomes or cost effectiveness of using these tools in a system of screening. For the purposes of guiding decision making about choice of screening tools, the current evidence is inadequate to gauge whether new technologies are "better" than conventional cytology..