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Does n-Acetylcysteine Amide exert Possible Neuroprotective Effects in Newborn Pigs after Perinatal Asphyxia?

Perinatal asphyxia and ensuing reoxygenation change the antioxidant capacity of cells and organs. To analyze the neuroprotective effect of the antioxidant N-acetylcysteine amide (NACA) after perinatal hypoxia-reoxygenation with an emphasis on proinflammatory cytokines and the transcription factor NF-x03BA;B in the prefrontal cortex of neonatal pigs. Twenty-nine newborn pigs, aged 12-36 h, were subjected to global hypoxia and hypercapnia. One sham-operated group (n = 5) and 2 experimental groups (n = 12) were exposed to 8% oxygen, until the base excess was -20 mmol/l or the mean arterial blood pressure fell to <20 mm Hg (asphyxia with NACA or saline). The pigs were observed for 9.5 h after hypoxia. Samples of prefrontal cortex and plasma were analyzed. Cortex: there was no significant difference in mRNA expression between the intervention groups regarding IL-1β, IL6, TNFα, MMP2, MMP9 or IL18. Pigs exposed to hypoxia-reoxygenation and treatment with NACA (NACA-pigs) had a significantly lower protein concentration of IL-1β than pigs treated with saline (placebo controls), i.e. 8.8 ± 3.9 versus 16.8 ± 10.5 pg/mg protein (p = 0.02). The activation of the transcription factor NF-x03BA;B (measured as the fold-change of phosphorylated p65Ser 536), was reduced in the NACA-pigs when compared to the placebo controls (5.2 ± 4.3 vs. 16.0 ± 13.5; p = 0.02). No difference between the intervention groups regarding brain histopathology or in the levels of 8-oxoguanine measured in the prefrontal cortex were observed. Plasma: the NACA-pigs had a stronger reduction of TNFα in the first 30 min following asphyxia compared with the placebo controls, i.e. 36 (30-44) versus 24 (14-32)% (p = 0.01).

The reduced levels of the pivotal inflammatory markers IL-1β and TNFα and the transcription factor NF-x03BA;B may indicate that NACA has possible neuroprotective effects after perinatal asphyxia.

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Does coaching of patients with an isolated minimally displaced fracture of the radial head immediately increase range of motion?

Prospective cohort. Elbow stiffness is the most common adverse event after isolated radial head fractures. To assess the effect of coaching on elbow motion during the same office visit in patients with such fractures. We enrolled 49 adult patients with minimally displaced radial head fractures, within 14 days of injury. After diagnosis, we measured demographics, catastrophic thinking, health anxiety, symptoms of depression, upper extremity-specific symptoms and disability, pain, and elbow and wrist motion. The patient was taught to apply an effective stretch in spite of the pain to limit stiffness, and elbow motion was measured again. With the exception of radial deviation and pronation, motion measures improved slightly but significantly on average immediately after coaching. Elbow flexion improved from 79% (110° ± 22°) of the uninjured side to 88% (122° ± 18°) after coaching (P < .001); elbow extension improved from 71% (29° ± 14°) to 78% (22° ± 15°) (P = .0012).

Instruction that stretching exercises are healthy even when painful resulted in immediate improvements in motion. Prospective studies comparing different strategies for coaching patients regarding painful stretches might help clarify the optimal approach.

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Do higher HPV16 and HPV18 Penile Viral Loads Are Associated With Decreased Human Papillomavirus Clearance in Uncircumcised Kenyan Men?

Whether higher penile human papillomavirus (HPV) viral load is associated with a lower rate of HPV clearance remains unknown. We examined the association between penile HPV16 and HPV18 viral load and subsequent HPV clearance in uncircumcised Kenyan men. Participants were human immunodeficiency virus (HIV)-seronegative, sexually active, 18- to 24-year-old men randomized to the control arm of a male circumcision trial in Kisumu, Kenya. Men provided exfoliated penile cells from two anatomical sites (glans/coronal sulcus and shaft) every 6 months for 2 years. GP5+/6+ polymerase chain reaction was used to identify 44 HPV-DNA types. Human papillomavirus viral load testing was conducted using a LightCyler real-time polymerase chain reaction assay; viral load was classified as high (>250 copies/scrape) or low (≤250 copies/scrape), for nonquantifiable values. The Kaplan-Meier method and Cox regression modeling were used to examine the association between HPV viral load and HPV clearance. A total of 1097 men, with 291 HPV16 and 131 HPV18 cumulative infections over 24 months were analyzed. Human papillomavirus clearance at 6 months after first HPV detection was lower for high versus low viral load HPV16 infections in the glans (adjusted hazard ratio [aHR], 0.65; 95% confidence interval [CI], 0.46-0.92)] and shaft (aHR, 0.44; 95% CI, 0.16-0.90), and HPV18 infections in the glans (aHR, 0.05; 95% CI, 0.01-0.17).

High versus low HPV viral load was associated with a reduced HPV clearance for HPV16 infections in the glans and shaft, and for HPV18 infections in the glans, among young uncircumcised men. Reduced clearance of high viral load HPV16 and HPV18 infections in men may increase HPV transmission to their female partners as well as enhance the development of penile lesions in comparison to men with low viral load HPV infections.

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Is aRT an alternative for restoring occlusoproximal cavities in primary teeth - evidence from an updated systematic review and meta-analysis?

A previous systematic review showed that atraumatic restorative treatment (ART) can be an option to restore the occlusoproximal cavities in primary teeth; however, few studies fulfilled the criteria of inclusion to generate a high level of evidence. To update the existing systematic review and address questions regarding survival rate of ART restorations compared to the conventional approach in occlusoproximal cavities in primary molars. The search was extended beyond the original search through the PubMed/MEDLINE database up to February 2016. Furthermore, Web of Science and EMBASE were searched. The inclusion criteria were subjects related to the scope of the systematic review. After selection by title and abstract, potentially eligible articles were read in full and included in accordance with exclusion criteria. Meta-analysis was carried out with the outcome being the survival rate of restorations. The search strategy identified 560 potentially relevant studies, in addition to 127 from the original systematic review. A total of four articles were included in the qualitative and quantitative analyses. Meta-analysis showed no statistically significant difference between ART and conventional approaches in survival rate of occlusoproximal cavities (OR = 0.887, 95% CI: 0.574-1.371).

ART restorations have similar survival rate compared to conventional treatment and can be considered an option to restore occlusoproximal cavities in primary molars.

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Does tERT promoter mutation predict radioiodine refractory in distant metastatic differentiated thyroid cancer?

Telomerase Reverse Transcriptase (TERT) promoter mutation has been reported to be associated with aggressive characteristics in differentiated thyroid cancer (DTC). This study examined the status of TERT promoter mutation in distant metastatic DTC (DM-DTC), and evaluated the correlation between TERT mutation and radioactive iodine-131(RAI) uptake, as well as that between TERT mutation and therapy response. TERT promoter and B-Raf proto-oncogene (BRAF) V600E mutation were retrospectively examined in primary tumors of 66 DM-DTC patients. Stimulated thyroglobulin (sTg) changes, RAI uptake status (avid or non-avid), and other imaging evidence were analyzed to evaluate therapy response. After a median follow-up of 46.5 months (interquartile range, 29.0 to 70.5 months), therapy response was classified as disease control and refractory. The prevalence of TERT mutations was 22.73% (15/66), of which C228T mutation was more prevalent (13/15) than C250T mutation (2/15). Rising sTg was noticed in 93.33% (14/15) of TERT mutation group. While in cases with both mutations negative, 78.12 % (25/32) presented with decreased sTg. TERT mutation closely correlated with poor RAI therapy response (p＜0.001), and all 15 patients were classified as refractory to RAI with a positive predictive value of 100% at the end point of follow-up. TERT mutation was associated with older mean age at diagnosis (p＜0.001), larger mean tumor diameter (P = 0.013), and more likelihood of both BRAF mutation coexistence (P = 0.044) and refractory to RAI (p＜0.001). In the 36 cases received imaging semi-quantitative analysis, it was found that TERT mutation significantly correlated with non-RAI-avidity, with a much lower mean tumor/background (T/B) ratio (obtained from post RAI therapy whole-body scanning) than TERT wild-type (p＜0.001). And DM-DTC patients with TERT mutation were more likely to lose RAI-avidity at initial RAI therapy than those with only BRAF mutation (8/8 vs 5/11, Fisher's exact test, P = 0.018).

TERT promoter mutation closely associates with non-RAI-avidity in DM-DTC, and when comparing with BRAF mutation, TERT mutation manifested a worse negative influence on RAI uptake. It could also be used as a predictive marker to early identify refractory to RAI.

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Does serum Thyroglobulin Concentration be a Weak Marker of Iodine Status in a Pregnant Population with Iodine Deficiency?

To assess the reliability of thyroglobulin (Tg) as a marker of iodine status during pregnancy. 299 women aged 30.5 ± 4.8 years (mean ± SD) were studied. In every subject, we measured urinary iodine concentration (UIC), serum thyrotropin (TSH), Tg, free thyroxine (fT4), Tg autoantibodies (TgAbs) and human chorionic gonadotropin (hCG) levels. We excluded samples with increased TgAbs from the analysis. According to WHO criteria, the study population was iodine deficient in every trimester. Serum Tg levels did not differ during the three trimesters of pregnancy. Serum hCG levels fell significantly as pregnancies advanced. A weak, significantly negative correlation (limited to the 3rd trimester) was found between Tg and UIC (ρ = -0.187, p = 0.039). Serum fT4 decreased as pregnancies advanced and TSH increased. Serum fT4 was negatively correlated with TSH (ρ = -0.161, p = 0.006) and positively with hCG (ρ = +0.165, p = 0.005). The multiple regression equation of Tg based on hCG, TSH, UIC and trimester of pregnancy was significant but weak (F = 4.057, p = 0.003; R(2) = 0.055), with hCG as a significant predictor Tg (p for log hCG = 0.041).

Tg cannot be considered as a valid marker of iodine deficiency in pregnancy, at least in a mildly iodine-deficient environment. Further studies in a larger patient cohort with differences in iodine status, as well as studies on Tg changes after improving iodine status in pregnant women, are needed in order to corroborate these results.

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Is familiar Papillary Thyroid Carcinoma in a Large Brazilian Family Associated with Succinate Dehydrogenase Defects?

Thyroid cancer is the most common endocrine gland malignancy. Advances in understanding the genetic basis for thyroid cancer revealed the potential involvement of several genes in the formation of thyroid tumors. Mutations in the gene coding for succinate dehydrogenase subtype B (SDHB) have been implicated in papillary thyroid cancer (PTC). Succinate dehydrogenase (SDH) is a heterotetrameric protein composed of four subunits, SDHA, SDHB, SDHC, and SDHD, and participates in both the electron transport chain and the tricarboxylic acid cycle. The aim of the study was to evaluate the association between variants in the SDHA, SDHB, SDHC, and SDHD genes and familiar PTC in a large Brazilian family. Four patients with PTC, 1 patient with PTC and gastrointestinal stromal tumor (GIST), 1 patient with GIST, and their relatives - several of them with different thyroid problems - from a large Brazilian family were screened for genetic variations of SDHx genes with the use of polymerase chain reaction-single-stranded conformational polymorphism and direct sequencing. Only one rare variation in SDHA was found in some of the family members, but not segregating with the disease. No other genetic variants of these genes were detected in the family members that presented with PTC and/or GIST.

Familiar PTC and a GIST were not associated with SDHx mutations; additional genetic defects, yet unknown, may be responsible for the development of tumor.

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Does valve interstitial cell tensional homeostasis direct calcification and extracellular matrix remodeling processes via RhoA signaling?

Valve interstitial cells are active and aggressive players in aortic valve calcification, but their dynamic mediation of mechanically-induced calcific remodeling is not well understood. The goal of this study was to elucidate the feedback loop between valve interstitial cell and calcification mechanics using a novel three-dimensional culture system that allows investigation of the active interplay between cells, disease, and the mechanical valve environment. We designed and characterized a novel bioreactor system for quantifying aortic valve interstitial cell contractility in 3-D hydrogels in control and osteogenic conditions over 14 days. Interstitial cells demonstrated a marked ability to exert contractile force on their environment and to align collagen fibers with the direction of tension. Osteogenic environment disrupted interstitial cell contractility and led to disorganization of the collagen matrix, concurrent with increased αSMA, TGF-β, Runx2 and calcific nodule formation. Interestingly, RhoA was also increased in osteogenic condition, pointing to an aberrant hyperactivation of valve interstitial cells mechanical activity in disease. This was confirmed by inhibition of RhoA experiments. Inhibition of RhoA concurrent with osteogenic treatment reduced pro-osteogenic signaling and calcific nodule formation. Time-course correlation analysis indicated a significant correlation between interstitial cell remodeling of collagen fibers and calcification events.

Interstitial cell contractility mediates internal stress state and organization of the aortic valve extracellular matrix. Osteogenesis disrupts interstitial cell mechanical phenotype and drives disorganization, nodule formation, and pro-calcific signaling via a RhoA-dependent mechanism.

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Does 2-cyclohexylamino-5,8-dimethoxy-1,4-naphthoquinone inhibit LPS-induced BV2 microglial activation through MAPK/NF-kB signaling pathways?

To verify the effects of several 5,8-dimethoxy-1,4-naphthoquinone (DMNQ) derivatives on LPS-induced NO production, cellular ROS levels and cytokine expression in BV-2 microglial cells. An MTT assay and FACS flow cytometry were performed to assess the cellular viability and apoptosis and cellular ROS levels, respectively. To examine the expression of pro-inflammatory cytokines and cellular signaling pathways, semi-quantitative RT-PCR and Western blotting were also used in this study. Among the six newly synthesized DMNQ derivatives, 2-cyclohexylamino-5,8-dimethoxy-1,4-naphthoquinone (R6) significantly inhibited the NO production, cellular ROS levels and the cytokines expression in BV-2 microglial cells, which stimulated by LPS. Signaling study showed that compound R6 treatment also significantly down-regulated the LPS-induced phosphorylation of MAPKs (ERK, JNK and p38) and decreased the degradation of IκB-α in BV2 microglial cells.

Our findings demonstrate that our newly synthesized compound derived from DMNQ, 2-cyclohexylamino-5,8-dimethoxy-1,4-naphthoquinone (R6), might be a therapeutic agent for the treatment of glia-mediated neuroinflammatory diseases.

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Does cLOSING MACULAR hole WITH `` MACULAR PLUG '' WITHOUT GAS TAMPONADE AND POSTOPERATIVE POSTURING?

To investigate the surgical results of macular hole surgery without gas tamponade or postoperative posturing in patients with Stage 3 and Stage 4 macular holes with ≥500 μm mean base diameter. Retrospective interventional case series. Twenty-six patients with Stage 3 and Stage 4 macular holes. Twenty-six eyes of 26 patients with Stage 3 and Stage 4 macular holes and a mean base diameter of 892.8 ± 349 μm underwent pars plana 23-gauge vitrectomy with broad internal limiting membrane peel (ILM peel), inverted ILM flap repositioning (ILMR), and use of autologous gluconated blood clumps as a macular plug to close the macular hole. No fluid-air exchange, endotamponade, or postoperative posturing was used. The subjects were followed up for 12 months. The anatomical outcome of the procedure was evaluated by fundus examination and optical coherence tomography. Spectral domain optical coherence tomography was used to study the restoration of the outer retinal layer integrity in the postoperative period. The preoperative and postoperative best-corrected visual acuities in logMAR units were compared to evaluate functional outcome. Macular hole closure and best-corrected visual acuity before and after surgery. Twenty-six patients with mean age 62.8 ± 7.3 years, preoperative median best-corrected visual acuity 6/60 (1.0 logMAR units), and a mean base diameter of 892.8 ± 349 μm underwent surgery to close macular holes without gas tamponade or postoperative posturing. Twenty patients (76.9%) were phakic. Twenty eyes (76.92%) had Stage 3 macular holes and 6 eyes (23.10%) had Stage 4 macular holes. After a single surgery, hole closure was achieved in 100% of eyes. The median best-corrected visual acuity improved from 6/60 (1.0 logMAR units) to 6/18 (0.50 logMAR units) (P < 0.001). Three patients needed cataract surgery at 12-month follow-up. No major intraoperative or postoperative complications were observed.

Twenty-three-gauge pars plana vitrectomy combined with broad ILM peeling, use of ILMR and autologous gluconated blood clumps as a macular plug is effective in achieving satisfactory hole closure with statically significant functional improvement for large Stage 3 and Stage 4 macular holes.

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Is palmitate-Induced MMP-9 Expression in the Human Monocytic Cells Mediated through the TLR4-MyD88 Dependent Mechanism?

Obese individuals are known to have increased Matrix metalloproteinase (MMP)-9 plasma levels and MMP-9 is reported to play an important role in obesity-associated adipose tissue inflammation. Since in obesity, the levels of circulatory saturated free fatty acid (FFA) palmitate (palimitic acid) are increased and modulate the expression of inflammatory mediators, the role of palmitate in the regulation of MMP-9 remains unclear. Human monocytic cell line THP-1 and primary monocytes were stimulated with palmitate and TNF-α (positive control). MMP-9 expression was assessed with real time RT-PCR and ELISA. Signaling pathways were studied by using THP-1-XBlue™ cells, THP-1-XBlue™-defMyD cells, anti-TLR4 mAb and TLR4 siRNA. Phosphorylation of NF-kB and c-Jun was analyzed by Western blotting. Here, we provide the evidence that palmitate induces MMP-9 expression at both mRNA (THP-1: 6.8 ± 1.2 Fold; P = 0.01; Primary monocytes: 5.9 ± 0.7 Fold; P = 0.0003) and protein (THP1: 1116 ±14 pg/ml; P<0.001; Primary monocytes: 1426 ± 13.8; P = 0.0005) levels in human monocytic cells. Palmitate-induced MMP-9 secretion was markedly suppressed by neutralizing anti-TLR-4 antibody (P < 0.05). Furthermore, genetic silencing of TLR4 by siRNA also significantly abrogated the palmitate-induced up-regulation of MMP-9. Additionally, MyD88-/- THP-1 cells did not express MMP-9 in response to palmitate treatment. Increased NF-κB/AP-1 activity (P<0.05) was also observed in palmitate-treated THP-1 cells.

Altogether, these results show that palmitate induces TLR4-dependent activation of MMP-9 gene expression, which requires the recruitment of MyD88 leading to activation of NF-kB/AP-1 transcription factors. Thus, our findings suggest that the palmitate-induced MMP-9 secretion might be an underlying mechanism of its increased levels in obesity and related metabolic inflammation.

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Does trans-pQTL study identify immune crosstalk between Parkinson and Alzheimer loci?

Given evidence from genetic studies, we hypothesized that there may be a shared component to the role of myeloid function in Parkinson and Alzheimer disease (PD and AD) and assessed whether PD susceptibility variants influenced protein expression of well-established AD-associated myeloid genes in human monocytes. We repurposed data in which AD-related myeloid proteins CD33, TREM1, TREM2, TREML2, TYROBP, and PTK2B were measured by flow cytometry in monocytes from 176 participants of the PhenoGenetic Project (PGP) and Harvard Aging Brain Study. Linear regression was used to identify associations between 24 PD risk variants and protein expression. The 2 cohorts were meta-analyzed in a discovery analysis, and the 4 most strongly suggestive results were validated in an independent cohort of 50 PGP participants. We discovered and validated an association between the PD risk allele rs12456492(G) in the RIT2 locus and increased CD33 expression (p joint = 3.50 × 10(-5)) and found strongly suggestive evidence that rs11060180(A) in the CCDC62/HIP1R locus decreased PTK2B expression (p joint = 1.12 × 10(-4)). Furthermore, in older individuals, increased CD33 expression on peripheral monocytes was associated with a greater burden of parkinsonism (p = 0.047), particularly bradykinesia (p = 6.64 × 10(-3)).

We find that the rs12456492 PD risk variant affects expression of AD-associated protein CD33 in peripheral monocytes, which suggests that genetic factors for these 2 diseases may converge to influence overlapping innate immune-mediated mechanisms that contribute to neurodegeneration. Furthermore, the effect of the rs12456492(G) PD risk allele on increased CD33 suggests that the inhibition of certain myeloid functions may contribute to PD susceptibility, as is the case for AD.

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Does cytosolic phospholipase A2 contribute to innate immune defense against Candida albicans lung infection?

The lung is exposed to airborne fungal spores, and fungi that colonize the oral cavity such as Candida albicans, but does not develop disease to opportunistic fungal pathogens unless the immune system is compromised. The Group IVA cytosolic phospholipase A2 (cPLA2α) is activated in response to Candida albicans infection resulting in the release of arachidonic acid for eicosanoid production. Although eicosanoids such as prostaglandins and leukotrienes modulate inflammation and immune responses, the role of cPLA2α and eicosanoids in regulating C. albicans lung infection is not understood. The responses of cPLA2α(+/+) and cPLA2α(-/-) Balb/c mice to intratracheal instillation of C. albicans were compared. After challenge, we evaluated weight loss, organ fungal burden, and the recruitment of cells and the levels of cytokines and eicosanoids in bronchoalveolar lavage fluid. The ability of macrophages and neutrophils from cPLA2α(+/+) and cPLA2α(-/-) mice to recognize and kill C. albicans was also compared. After C. albicans instillation, cPLA2α(+/+) mice recovered a modest weight loss by 48 h and completely cleared fungi from the lung by 12 h with no dissemination to the kidneys. In cPLA2α(-/-) mice, weight loss continued for 72 h, C. albicans was not completely cleared from the lung and disseminated to the kidneys. cPLA2α(-/-) mice exhibited greater signs of inflammation including higher neutrophil influx, and elevated levels of albumin and pro-inflammatory cytokines/chemokines (IL1α, IL1β, TNFα, IL6, CSF2, CXCL1, CCL20) in bronchoalveolar lavage fluid. The amounts of cysteinyl leukotrienes, thromboxane B2 and prostaglandin E2 were significantly lower in bronchoalveolar lavage fluid from C. albicans-infected cPLA2α(-/-) mice compared to cPLA2α(+/+) mice. Alveolar macrophages and neutrophils from uninfected cPLA2α(-/-) mice exhibited less killing of C. albicans in vitro than cells from cPLA2α(+/+) mice. In addition alveolar macrophages from cPLA2α(-/-) mice isolated 6 h after instillation of GFP-C. albicans contained fewer internalized fungi than cPLA2α(+/+) macrophages.

The results demonstrate that cPLA2α contributes to immune surveillance and host defense in the lung to prevent infection by the commensal fungus C. albicans and to dampen inflammation.

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Is the leishmanicidal activity of oleuropein selectively regulated through inflammation- and oxidative stress-related genes?

Much research effort has been focused on investigating new compounds derived from low-cost sources, such as natural products, for treating leishmaniasis. Oleuropein derived from numerous plants, particularly from the olive tree, Olea europaea L. (Oleaceae), is a biophenol with many biological activities. Our previous findings showed that oleuropein exhibits leishmanicidal effects against three Leishmania spp. in vitro, and minimizes the parasite burden in L. donovani-infected BALB/c mice. The aim of the present study is to investigate the possible mechanism(s) that mediate this leishmanicidal activity. We determined the efficacy of oleuropein in elevating ROS and NO production in L. donovani-infected J774A.1 macrophages and in explanted splenocytes and hepatocytes obtained from L. donovani-infected BALB/c mice. We also assessed the expression of genes that are related to inflammation, T-cell polarization and antioxidant defense, in splenocytes. Finally, we determined the ratios of specific IgG2a/IgG1 antibodies and DTH reactions in L. donovani-infected BALB/c mice treated with oleuropein. Oleuropein was able to elevate ROS production in both in vitro and in vivo models of visceral leishmaniasis and raised NO production in ex vivo cultures of splenocytes and hepatocytes. The extensive oxidative stress found in oleuropein-treated mice was obviated by the upregulation of the host's antioxidant enzyme (mGCLC) and the simultaneous downregulation of the corresponding enzyme of the parasite (LdGCLC). Moreover, oleuropein was able to mount a significant Th1 polarization characterized by the expression of immune genes (IL-12β, IL-10, TGF-β1, IFN-γ) and transcription factors (Tbx21 and GATA3). Moreover, this immunomodulatory effect was also correlated with an inhibitory effect on IL-1β gene expression, rather than with the expression of IL-1α, IL-1rn and TNF-α. Furthermore, oleuropein-treated BALB/c mice mounted a delayed-type hypersensitivity (DTH) response and an elevated Leishmania-specific IgG2a/IgG1 ratio that clearly demonstrated an in vivo protective mechanism.

The ability of Oleuropein to promote a Th1 type immune response in L. donovani-infected BALB/c mice points towards the candidacy of this bioactive compound as an immunomodulatory agent that may complement therapeutic approaches to leishmaniasis.

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Does addition of Dexamethasone alter the Bile Acid Composition by Inducing CYP8B1 in Primary Cultures of Human Hepatocytes?

Primary human hepatocytes offer the best human in vitro model for studies on human liver cell metabolism. Investigators use a variety of different media supplements and matrix biocoatings and the type of culture system used may influence the outcome. To optimize in vitro conditions for primary human hepatocytes with regard to bile acid synthesis. Human hepatocytes were isolated and cultured on collagen type I or EHS matrigel in cell media with or without dexamethasone. The glucocorticoid receptor (GR) antagonist RU486 was used to elucidate the involvement of GR. Hepatocytes cultured on EHS matrigel produced more bile acids and expressed higher levels of cholesterol 7α-hydroxylase (CYP7A1) than cells cultured on rat tail collagen. Supplementation with dexamethasone increased the formation of cholic acid (CA) and decreased chenodeoxycholic acid formation. In line with these results, the mRNA expression of sterol 12α-hydroxylase (CYP8B1) increased following dexamethasone treatment. Surprisingly, the mRNA expression of CYP7A1 and CYP27A1 was not increased to the same extent. By using the GR antagonist RU486, we concluded that CYP8B1 induction is mediated via a GR-independent pathway. An altered expression of retinoid-related orphan receptor (ROR) α and ROR α target gene Glucose-6-phosphatase (G6Pase) suggests that ROR α signaling may regulate CYP8B1 expression.

Primary human hepatocytes have an increased bile acid synthesis rate when cultured on matrigel as compared to collagen. Exposure to glucocorticoid hormones stimulates the expression of CYP8B1, leading to an increased formation of CA and alteration of the bile acid composition. The effect is most likely mediated through a GR-independent pathway, possibly through ROR α.

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Does benzoate fraction from Gentiana rigescens Franch alleviate scopolamine-induced impaired memory in mice model in vivo?

G. rigescens Franch (Long Dan Cao in Chinese) is a well-known TCM herb. It is clinically used with other drugs for the treatment of brain diseases such as epilepsy, postherpetic neuralgia in China. In our previous study, the 11 dihydroxybenzoates compounds with NGF mimicking activity from G. rigescens Franch were found. In the present study, the neurogenesis and neuroprotection of a mixture of benzoates ( n-GS) were investigated in animal level. The NGF mimicking activity of n-GS from G. rigescens Franch was examined in PC12 cells. The neurogenesis effects of n-GS were investigated in ICR mice with 5-bromo-2-deoxyuridine (BrdU) and neuronal neclei (NeuN) double immunostaining. Furthermore, the neuroprotection effects of n-GS on the memory in a scopolamine (SCO)-induced mouse model were evaluated with animal behavior tests. The NGF-mimicking function and neurogenesis of n-GS were observed in PC12 cells and in normal mice. Subsequently, we investigated the effects of n-GS on the memory in a SCO-induced mouse model. In Y-maze test, SCO significantly lowered the alternation. This finding was reversed by n-GS and donepezil (DONE). SCO significantly impaired the mice's performance in novel object recognition (NOR) and Morris water maze (MWM) tests. The time spent to explore the novel object was longer in the n-GS- and DONE-treated groups than in the SCO control group. In the MWM test, the escape latency of n-GS- and DONE-treated groups was shorter than that of the SCO control group. Mechanism study showed that SCO significantly reduced superoxide dismutase (SOD) but increased the activities of acetylcholinesterase (AChE) and the levels of malondialdehyde (MDA) in the hippocampus and cerebral cortex, which all can be improved by n-GS and DONE. Additionally, the phosphorylation of type 1 insulin-like growth factor (IGF-1) receptor, extracellular signal-regulated kinase (ERK), and cAMP responsive element-binding (CREB) protein in the hippocampus was significantly up-regulated in the treatment group compared with that in the SCO group.

n-GS could alleviate impaired memory of the SCO-induced mice model by inhibiting AChE activity and oxidative stress, and regulating the IGF-1R/ERK signaling pathway.

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Does silencing Drp1 inhibit glioma cells proliferation and invasion by RHOA/ ROCK1 pathway?

Dynamin-related protein 1 (Drp1) is a newly discovered therapeutic target for tumor initiation, migration, proliferation, and chemosensitivity. In the present study, we aimed to examine the level of expression and distribution of DRP1 in glioma tissues and explore the concrete mechanism of DRP1 played in glioma. Expression of DRP1 in glioma tissues was determined by immunohistochemistry staining. The DRP1 gene was knocked down using small interfering RNA, and was overexpressed using plasmids in glioma cells. To assess changes in cell function, in vitro assays for invasion and growth were applied. Protein expression was tested by using Western-blot method. Variation of F-actin in cells was analyzed using immunofluorescence staining. Interactions between proteins were determined by co-immunoprecipitation. The protein expression levels of DRP1 were significantly increased in glioma tissues compared to the normal brain tissues. Down-regulation of DRP1 decreased cell proliferation and invasion, and inhibited the formation of pseudopodias and microvillis. Moreover, a possible link between DRP1 and RHOA was confirmed when interactions between these two proteins were observed in the cells.

Our results demonstrated that silencing DRP1 regulated the cytoskeleton remodeling through inhibiting RHOA/ROCK1 pathway, and thus decreased the proliferation and invasion of glioma cells.

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Does specific locations of linear furrow in patients with esophageal eosinophilia?

Linear furrows are the most frequently found endoscopic abnormality in patients with esophageal eosinophilia (EE); however, the precise endoscopic features remain to be fully elucidated. Here, we aimed to clarify the endoscopic features of EE, essential for the diagnosis of eosinophilic esophagitis (EoE), by focusing on the specific locations of linear furrows in a Japanese population. We enrolled 70 cases with EE (≥15 eosinophils/high-power field) who were diagnosed at our hospital and related facilities. Information regarding endoscopic findings and clinical parameters was retrospectively reviewed. Next, the position of linear furrows in relation to esophageal longitudinal folds (ridge or valley) was evaluated in each case and compared with the position of mucosal breaks in patients with reflux esophagitis. Finally, the relationship between linear furrows and eosinophilic infiltration was evaluated. Of the 70 EE patients, 63 (90%) had linear furrows. Those occurred in a radial pattern and were widespread throughout the lower to upper esophagus, and exclusively found in esophageal longitudinal mucosal fold valleys, not on ridges, which was different from the position of mucosal breaks in patients with reflux esophagitis. Increased eosinophilic infiltration was significantly more frequent in linear furrows in the valleys (93%) as compared to mucosa on adjacent ridges (60%) (P < 0.05).

Investigation of these endoscopic characteristics, especially by focusing on linear furrows in esophageal mucosal fold valleys, may provide important clues for more accurate diagnosis of EoE.

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Does early remission status predict long-term outcomes in patients with Crohn 's disease treated with certolizumab pegol?

In Crohn's disease (CD), rapid response to anti-tumor necrosis factor therapy improves short- and medium-term outcomes, but the relationship between early remission (ER) and long-term remission is unclear. This exploratory analysis of PRECiSE 3 (NCT00160524) assessed whether ER after initiation of certolizumab pegol predicted long-term remission. Patients enrolled in PRECiSE 3 had completed PRECiSE 1 or 2, two randomized placebo-controlled studies for moderate to severe CD, and received open-label certolizumab pegol 400 mg every 4 weeks for a total treatment duration of ≤7.5 years. Time to loss of remission between patients with and without ER (Harvey-Bradshaw Index ≤4 at or before Week 6 of PRECiSE 1 or 2) was compared by log-rank test of Kaplan-Meier estimates. At baseline, patients with (n = 242) and without (n = 148) ER had mean (standard deviation [SD]) durations of CD of 6.8 (6.6) and 7.4 (7.8) years, mean (SD) CD Activity Index scores of 280.3 (53.4) and 311.1 (55.5), with 45.5% and 41.9% of patients having ileocolonic CD, and median C-reactive protein concentrations of 8.0 and 5.0 mg/L, respectively. Median certolizumab pegol plasma concentrations during the first 6 weeks of therapy were similar in both groups. Mean time to loss of remission was significantly longer in patients with versus without ER (2.77 vs. 1.14 years, p < 0.0001).

In certolizumab pegol-treated patients with CD, ER appears to be an important predictor of long-term clinical remission. Prospective trials are needed to determine whether ER improves other long-term outcomes.

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Do distinct resting-state perfusion patterns underlie psychomotor retardation in unipolar vs. bipolar depression?

Psychomotor abnormalities characterize both unipolar (UP) depression and bipolar (BP) depression. We aimed to assess their neurobiological correlates in terms of motor activity (AL) and resting-state cerebral blood flow (rCBF) and investigate their association in BP, UP, and healthy controls (HC). We enrolled 42 depressed patients (22 BP, 20 UP) and 19 HC matched for age, gender, education, income. AL and rCBF were objectively assessed with the use of wrist actigraphy and arterial spin labeling. Group differences and the association of AL and rCBF were computed. Activity level was significantly reduced in patients, but no difference was found between BP and UP. Increased perfusion was found in BP compared with UP and HC, in multiple brain areas. We found positive correlations of rCBF and AL in BP and UP, in different parts of the insula and frontal regions. Only BP showed a cluster in the left precentral gyrus. In HC, only inverse correlations of AL and rCBF were found.

The differences in rCBF and in the localization of the clusters of positive AL/rCBF correlations between BP and UP suggest that different neural impairments may underlie motor symptoms in the two disorders, but finally converge in phenotypically similar manifestations.

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Do cpG site methylation in CRYAA promoter affect transcription factor Sp1 binding in human lens epithelial cells?

Age-related cataract (ARC) is the leading cause of visual impairment worldwide, and α-crystallin (CRYAA) is the predominant structural protein involved in the maintenance of lens clarity and refractive properties. We previously demonstrated that CRYAA genes undergo epigenetic repression in the lens epithelia in ARC. We further analyze the underlying mechanism in the current study. The transcription factor binding sites of the CpG island of CRYAA promoter were predicted by TESS website. An electrophoretic mobility shift assay (EMSA) was used to analyze the impact of the methylation of CpG sites on transcription factors. Human lens epithelial B-3 (HLE B-3) Cells were treated with demethylation agent zebularine in the concentrations of 0 (PBS as control), 10 μM, 20 μM, 50 μM, 100 μM and 200 μM, respectively. After treatment in the above concentrations for 24 h, 48 h and 72 h, respectively, CRYAA mRNA expression levels were detected by Quantitative Real-Time RT-PCR. The methylation of the CpG site of the CRYAA promoter decreased the DNA-binding capacity of transcription factor Sp1. Zebularine increased CRYAA expression in HLE B-3 Cells in a dose- dependent and time- dependent pattern.

The evidence presented suggests that the methylation of the CpG sites of the CRYAA promotor directly affect Sp1 binding, leading to down expression of CRYAA in human lens epithelial cells. Zebularine treatment could restore CRYAA expression in a dose- dependent and time- dependent pattern.

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Does microRNA-34b mediate hippocampal astrocyte apoptosis in a rat model of recurrent seizures?

Recurrent convulsions can cause irreversible astrocyte death, impede neuron regeneration, and further aggravate brain damage. MicroRNAs have been revealed as players in the progression of numerous diseases including cancer and Alzheimer's disease. Particularly, microRNA has been found linked to seizure-induced neuronal death. In this study, a rat model of recurrent convulsions induced by flurothyl treatments was utilised to assess the alterations of microRNA expressions in hippocampus tissues. We also applied an in vitro model in which primary astrocytes were exposed to kainic acid to verify the targets of miR-34b-5p identified in the animal model. We discovered that miR-34b-5p, a member of the miR-34 family, increased significantly in flurothyl-treated rat hippocampus tissue. More surprisingly, this upregulation occurred concurrently with accumulating astrocyte apoptosis, indicating the involvement of miR-34b-5p in seizures caused astrocyte apoptosis. Results from the in vitro experiments further demonstrated that miR-34b-5p directly targeted Bcl-2 mRNA, translationally repressed Bcl-2 protein, and thus modulated cell apoptosis by influencing Bcl-2, Bax, and Caspase-3.

Our findings prove microRNAs play a role in mediating recurrent convulsions-induced astrocyte death and further indicate that miR-34b-5p could acts as a regulator for astrocyte apoptosis induced by recurrent seizures.

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Is the POR rs1057868-rs2868177 GC-GT diplotype associated with high tacrolimus concentrations in early post-renal transplant recipients?

Cytochrome P450 oxidoreductase (POR) is the only flavoprotein that donates electrons to all microsomal P450 enzymes (CYP), and several POR SNPs have been shown to be important contributors to altered CYP activity or CYP-mediated drug metabolism. In this study we examined the association between 6 POR SNPs and tacrolimus concentrations in Chinese renal transplant recipients. A total of 154 renal transplant recipients were enrolled. Genotyping of CYP3A5*3 and 6 POR SNPs was performed. All patients received a triple immunosuppressive regimen comprising tacrolimus, mycophenolate mofetil and prednisone. Dose-adjusted tacrolimus trough concentrations were obtained on d 7 (C0D7/D) after transplantation when steady-state concentration of tacrolimus was achieved (dosage had been unchanged for more than 3 d). Tacrolimus C0D7/D in CYP3A5*3/*3/ POR rs1057868-rs2868177 GC-GT diplotype carriers was 1.62- and 2.72-fold higher than those in CYP3A5*3/*3/ POR rs1057868-rs2868177 GC-GT diplotype non-carriers and CYP3A5*1 carriers (220.17±48.09 vs 135.69±6.86 and 80.84±5.27 ng/mL/mg/kg, respectively, P<0.0001). Of CYP3A5*3/*3/ POR rs1057868-rs2868177GC-GT diplotype carriers, 85.71% exceeded the upper limit of the target range (8 ng/mL), which was also significantly higher compared with the latter two groups (14.29% and 0.00%, respectively, P<0.0001). The CYP3A5*3 and POR rs1057868-rs2868177 GC-GT diplotype explained 31.7% and 5.7%, respectively, of the inter-individual variability of tacrolimus C0D7/D, whereas the POR rs1057868-rs2868177 GC-GT diplotype could explain 10.9% of the inter-individual variability of tacrolimus C0D7/D in CYP3A5 non-expressers.

The CYP3A5*3 and POR rs1057868-rs2868177 GC-GT diplotype accounted for the inter-individual variation of tacrolimus C0D7/D. Genotyping of POR rs1057868-rs2868177 diplotypes would help to differentiate initial tacrolimus dose requirements and to achieve early target C0 ranges in Chinese renal transplant recipients.

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Does sweroside ameliorate α-naphthylisothiocyanate-induced cholestatic liver injury in mice by regulating bile acids and suppressing pro-inflammatory responses?

Sweroside is an iridoid glycoside with diverse biological activities. In the present study we investigated the effects of sweroside on α-naphthylisothiocyanate (ANIT)-induced cholestatic liver injury in mice. Mice received sweroside (120 mg·kg(-1)·d(-1), ig) or a positive control INT-747 (12 mg·kg(-1)·d(-1), ig) for 5 d, and ANIT (75 mg/kg, ig) was administered on d 3. The mice were euthanized on d 5, and serum biochemical markers, hepatic bile acids and histological changes were analyzed. Hepatic expression of genes related to pro-inflammatory mediators and bile acid metabolism was also assessed. Primary mouse hepatocytes were exposed to a reconstituted mixture of hepatic bile acids, which were markedly elevated in the ANIT-treated mice, and the cell viability and expression of genes related to pro-inflammatory mediators were examined. Administration of sweroside or INT-747 effectively ameliorated ANIT-induced cholestatic liver injury in mice, as evidenced by significantly reduced serum biochemical markers and attenuated pathological changes in liver tissues. Furthermore, administration of sweroside or INT-747 significantly decreased ANIT-induced elevation of individual hepatic bile acids, such as β-MCA, CA, and TCA, which were related to its effects on the expression of genes responsible for bile acid synthesis and transport as well as pro-inflammatory responses. Treatment of mouse hepatocytes with the reconstituted bile acid mixture induced significant pro-inflammatory responses without affecting the cell viability.

Sweroside attenuates ANIT-induced cholestatic liver injury in mice by restoring bile acid synthesis and transport to their normal levels, as well as suppressing pro-inflammatory responses.

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Is snack intake reduced using an implicit , high-level construal cue?

Priming a high level construal has been shown to enhance self-control and reduce preference for indulgent food. Subtle visual cues have been shown to enhance the effects of a priming procedure. The current study therefore examined the combined impact of construal level and a visual cue reminder on the consumption of energy-dense snacks. A student and community-based adult sample with a wide age and body mass index (BMI) range (N = 176) were randomly assigned to a high or low construal condition in which a novel symbol was embedded. Afterward participants completed a taste test of ad libitum snack foods in the presence or absence of the symbol. The high (vs. the low) construal level prime successfully generated more abstract responses (p < .0001) and reduced intake when the cue-reminder was present (p = .02) but not when it was absent (p = .40).

Priming high construal level thinking reduces consumption of high energy dense snacks in the presence of a visual cue-reminder. This may be a practical technique for reducing overeating and has the potential to be extended to other unhealthy behaviors. (PsycINFO Database Record

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Is pTEN loss associated with a poor response to trastuzumab in HER2-overexpressing gastroesophageal adenocarcinoma?

Although trastuzumab improves the outcome of patients with human epidermal growth factor receptor 2 (HER2)-overexpressing gastric or gastroesophageal junction adenocarcinoma (collectively referred to as "gastroesophageal adenocarcinoma"; GEA), no clinical response is observed in a substantial population of patients. A predictive biomarker of trastuzumab response is required. The aim of this study was to evaluate whether the hyperactivation of the downstream phosphatidylinositol 3-kinase pathway, due to phosphatase and tensin homolog (PTEN) loss or PIK3CA mutations, could provide trastuzumab resistance in GEA. Expression of HER2 and PTEN, and PIK3CA gene mutations were screened in 264 surgically resected GEA specimens. The effects of PTEN knockdown on the response to trastuzumab on cell viability, HER2 downstream signaling, apoptosis, and cell cycle were evaluated in HER2-overexpressing NCI-N87 gastric adenocarcinoma and OE19 esophageal adenocarcinoma cell lines. Inhibition of xenograft tumor growth by trastuzumab was investigated in OE19 cells with or without PTEN knockdown. The PTEN expression and objective response were analyzed in 23 GEA patients who received trastuzumab-based therapy. PTEN loss was identified in 34.5 % of HER2-overexpressing GEA patients, whereas PIK3CA mutations were rare (5.6 %). Trastuzumab-mediated growth suppression, apoptosis, and G

PTEN loss was frequently found in HER2-overexpressing tumors, and was associated with a poor response to trastuzumab-based therapy in patients with GEA.

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Does orthogeriatric co-management improve the outcome of long-term care residents with fragility fractures?

Fragility fractures are a major health care problem worldwide. Both hip and non-hip fractures are associated with excess mortality in the years following the fracture. Residents of long-term nursing homes represent a special high-risk group for poor outcomes. Orthogeriatric co-management models of care have shown in multiple studies to have medical as well as economic advantages, but their impact on this high-risk group has not been well studied. We studied the outcome of long-term care residents with hip and non-hip fractures admitted to a geriatric fracture center. The study design is a single center, prospective cohort study at a level-I trauma center in Austria running a geriatric fracture center. The cohort included all fragility fracture patients aged over 70 admitted from a long-term care residence from May 2009 to November 2011. The data set consisted of 265 patients; the mean age was 86.8 ± 6.7 years, and 80 % were female. The mean follow-up after the index fracture was 789 days, with a range from 1 to 1842 days. Basic clinical and demographic data were collected at hospital admission. Functional status and mobility were assessed during follow-up at 3, 6, and 12 months. Additional outcome data regarding readmissions for new fractures were obtained from the hospital information database; mortality was crosschecked with the death registry from the governmental institute of epidemiology. 187 (70.6 %) patients died during the follow-up period, with 78 patients (29.4 %) dying in the first year. The mean life expectancy after the index fracture was 527 (±431) days. Differences in mortality rates between hip and non-hip fracture patients were not statistically significant. Compared to reported mortality rates in the literature, hip fracture patients in this orthogeriatric-comanaged cohort had a significantly reduced one-year mortality [OR of 0.57 (95 % CI 0.31-0.85)]. After adjustment for confounders, only older age (OR 1.091; p = 0.013; CI 1.019-1.169) and a lower Parker Mobility Scale (PMS) (OR 0.737; p = 0.022; CI 0.568-0.957) remained as independent predictors. During follow-up, 62 patients (23.4 %) sustained at least one subsequent fracture, and 10 patients (3.4 %) experienced multiple fractures; 29 patients (10.9 %) experienced an additional fracture within the first year. Nearly, half (47.1 %) regained their pre-fracture mobility based on the PMS.

Despite the generally poor outcomes for fragility fracture patients residing in long-term care facilities, orthogeriatric co-management appears to improve the outcome of high-risk fragility fracture patients. One-year mortality was 29.4 % in this cohort, significantly lower than in comparable trials. Orthogeriatric co-management may also have positive impacts on both functional outcome and the risk of subsequent fractures.

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Does lipid Emulsion Formulation of Parenteral Nutrition affect Intestinal Microbiota and Host Responses in Neonatal Piglets?

Total parenteral nutrition (TPN) is a cause of intestinal microbial dysbiosis and impaired gut barrier function. This may contribute to life-threatening parenteral nutrition-associated liver disease and sepsis in infants. We compared the effects of a lipid emulsion containing long-chain ω-3 polyunsaturated fatty acids (PUFAs; SMOFlipid) and a predominantly ω-6 PUFA emulsion (Intralipid) on microbial composition and host response at the mucosal surface. Neonatal piglets were provided isocaloric, isonitrogenous TPN for 14 days versus sow-fed (SF) controls. Equivalent lipid doses (10 g/kg/d) were given of either SMOFlipid (ML; n = 10) or Intralipid (SO; n = 9). Ileal segments and mucosal scrapings were used to characterize microbial composition by 16S rRNA gene sequencing and quantitative gene expression of tight junction proteins, mucins, antimicrobial peptides, and inflammatory cytokines. The microbial composition of TPN piglets differed from SF, while ML and SO differed from each other (analysis of molecular variance; P < .05); ML piglets were more similar to SF, as indicated by UniFrac distance (P < .05). SO piglets showed a specific and dramatic increase in Parabacteroides (P < .05), while ML showed an increase in Enterobacteriaceae (P < .05). Gene expression of mucin, claudin 1, β-defensin 2, and interleukin 8 were higher in TPN; overall increases were significantly less in ML versus SO (P < .05).

The formulation of parenteral lipid is associated with differences in the gut microbiota and host response of TPN-fed neonatal piglets. Inclusion of ω-3 long-chain PUFAs appears to improve host-microbial interactions at the mucosal surface, although mechanisms are yet to be defined.

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Does thrombomodulin enhance complement regulation through strong affinity interactions with factor H and C3b-Factor H complex?

Coagulation and complement systems are simultaneously activated at sites of tissue injury, leading to thrombin generation and opsonisation with C3b. Thrombomodulin (TM) is a cell-bound regulator of thrombin activation, but can also enhance the regulatory activity of complement factor H (FH), thus accelerating the degradation of C3b into inactive iC3b. This study sought to determine the biophysical interaction affinities of two recombinant TM analogs with thrombin, FH and C3b in order to analyze their ability to regulate serum complement activity. Surface plasmon resonance (SPR) analysis was used to determine binding affinities of TM analogs with FH and C3b, and compared to thrombin as positive control. The capacity of the two recombinant TM analogs to regulate complement in serum was tested in standard complement hemolytic activity assays. SPR analysis showed that both TM analogs bind FH and C3b-Factor H with nanomolar and C3b with micromolar affinity; binding affinity for its natural ligand thrombin was several fold higher than for FH. At a physiological relevant concentration, TM inhibits complement hemolytic activity in serum via FH dependent and independent mechanisms.

TM exhibits significant binding affinity for complement protein FH and C3b-FH complex and its soluble form is capable at physiologically relevant concentrations of inhibiting complement activation in serum.

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Do development of myotendinous-like junctions that anchor cardiac valves requires fibromodulin and lumican?

There are many patients that exhibit connective tissue related cardiac malformations but do not have mutations in collagen genes. The Small Leucine Rich Proteoglycans (SLRP) fibromodulin (FMOD) and lumican (LUM) bind collagen and regulate fibril assembly in other biological contexts. FMOD deficient mice and double deficient FMOD; LUM mice exhibited anomalies in regions where cardiac valve tissue interdigitates with adjacent muscle for support. Ectopic connective and/or myocardial tissue(s) was associated with the more severe cardiac valve anomalies in FMOD; LUM deficient mice. At postnatal day 0 (P0) there was an increase in the mesenchymal cell number in the regions where valve cusps anchor in FMOD; LUM deficient mice compared to WT. The cardiac valve anomalies correlated with the highest levels of FMOD expression in the heart and also where myotendinous junctions (MTJ) components biglycan, collagen type I alpha 1, and collagen type VI, are also localized.

The postnatal assembly of the collagen-rich ECM in regions where cardiac valves anchor, that we have designated 'myotendinous-like junctions' (MTLJ) requires the SLRPs FMOD and LUM. Moreover, FMOD and LUM may facilitate mesenchymal cell differentiation in late stages of cardiac valve development. Developmental Dynamics 245:1029-1042, 2016. © 2016 Wiley Periodicals, Inc.

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Is methylglyoxal associated with changes in kidney function among individuals with screen-detected Type 2 diabetes mellitus?

The glycolysis-derived metabolite methylglyoxal has been linked to clinical microvascular complications, including diabetic nephropathy. We aimed to further investigate the hypothesis that methylglyoxal is involved in decline in renal function by assessing the associations between measures of renal function during a 6-year follow-up in 1481 people with screen-detected Type 2 diabetes, as part of the Danish arm of the ADDITION-Europe trial (ADDITION-DK). Biobank serum samples collected at ADDITION-DK baseline (2001-2006) and follow-up (2009-2010) were used in the current analysis of methylglyoxal. We assessed cross-sectional baseline and longitudinal associations between methylglyoxal and urinary albumin-to-creatinine ratio (ACR) or estimated GFR (eGFR), and between methylglyoxal and categories of albuminuria or reduced eGFR. Baseline methylglyoxal was positively associated with ACR at baseline (12% higher ACR per doubling in methylglyoxal levels), and change in methylglyoxal during 6 years of follow-up was inversely associated with change in eGFR (-1.6 ml/min/1.73 m

In a population of people with screen-detected Type 2 diabetes, we observed associations between methylglyoxal and markers of renal function: 6-year change in methylglyoxal was inversely associated with 6-year change in eGFR. Also, methylglyoxal at baseline was positively associated with ACR at baseline. Our study lends further support to a role for methylglyoxal in the pathogenesis of diabetic nephropathy.

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Is the induction of CXCR4 expression in human osteoblast-like cells ( MG63 ) by CoCr particles regulated by the PLC-DAG-PKC pathway?

Osteolysis which leads to aseptic loosening of implants is a fundamental problem in joint replacement surgery (arthroplasty) and the leading cause for implant failure and revision surgery. Metal (CoCr) particles separated from implants by wear cause osteolysis and the failure of orthopedic implants, but the molecular mechanism is not clear. The chemokine receptor CXCR4 has been shown to play a pivotal role in periprosthetic osteolysis. The aim of this study was to determine which signal transduction pathway (PLC-DAG-PKC or MAPK/ERK) induces CXCR4 expression in osteoblast-like cells (MG63) cells. MG63 and Jurkat cells were stimulated with different amounts of particles (10 Real-time PCR data showed that CXCR4 mRNA expression in MG63 cells induced by CoCr particles was significantly diminished by the PKC-specific inhibitor chelerythrine. This effect was not observed with the MAPK/ERK inhibitor PD98059. The involvement of PKC was also confirmed by an intensified phosphorylation pattern after stimulation with CoCr particles. In Jurkat cells, none of the inhibitors exhibited any effect.

The induction of CXCR4-specific mRNA expression in MG63 cells after stimulation with CoCr particles is regulated by the PLC-DAG-PKC pathway and not by the MAPK/ERK pathway. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 2016.

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Does histological examination confirm clinical clearance of actinic keratoses following treatment with ingenol mebutate 0·05 % gel?

To date, studies with ingenol mebutate gel have used clinical clearance, not histological clearance, as a primary efficacy endpoint. This phase I, multicentre, single-arm, open-label study sought to confirm histologically the clinical clearance of actinic keratoses (AKs) to support a treatment effect deep in the epidermis. Patients (n = 108) aged ≥ 18 years with histologically confirmed AK within a 25-cm The observed agreement rate between clinical and histological assessments of clearance of a single AK was 81·9% and the positive predictive value of a clinical assessment of clearance was 87%. Agreement between the two pathologists was 88%. The common composite 8-week complete clearance rate was 41% (95% confidence interval 32-50). Observed agreement rates between RCM and pathologist I and II assessments of clearance were 72·9% and 81·4%, respectively. Overall, 30 patients (27·8%) experienced 38 adverse events (AEs). Application-site pain (four patients, 3·7%) was the most common treatment-related AE inside the treatment area.

Ingenol mebutate achieves histopathological clearance of AKs that correlates with observed clinical clearance. Clinical clearance is a good predictor for histological clearance.

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Is acid Sphingomyelinase ( ASM ) a Negative Regulator of Regulatory T Cell ( Treg ) Development?

Regulatory T cell (Treg) is required for the maintenance of tolerance to various tissue antigens and to protect the host from autoimmune disorders. However, Treg may, indirectly, support cancer progression and bacterial infections. Therefore, a balance of Treg function is pivotal for adequate immune responses. Acid sphingomyelinase (ASM) is a rate limiting enzyme involved in the production of ceramide by breaking down sphingomyelin. Previous studies in T-cells have suggested that ASM is involved in CD28 signalling, T lymphocyte granule secretion, degranulation, and vesicle shedding similar to the formation of phosphatidylserine-exposing microparticles from glial cells. However, whether ASM affects the development of Treg has not yet been described. Splenocytes, isolated Naive T lymphocytes and cultured T cells were characterized for various immune T cell markers by flow cytometery. Cell proliferation was measured by Carboxyfluorescein succinimidyl ester (CFSE) dye, cell cycle analysis by Propidium Iodide (PI), mRNA transcripts by q-RT PCR and protein expression by Western Blotting respectively. ASM deficient mice have higher number of Treg compared with littermate control mice. In vitro induction of ASM deficient T cells in the presence of TGF-β and IL-2 lead to a significantly higher number of Foxp3+ induced Treg (iTreg) compared with control T-cells. Further, ASM deficient iTreg has less AKT (serine 473) phosphorylation and Rictor levels compared with control iTreg. Ceramide C6 led to significant reduction of iTreg in both ASM deficient and WT mice. The reduction in iTreg leads to induction of IL-1β, IL-6 and IL-17 but not IFN-γ mRNA levels.

ASM is a negative regulator of natural and iTreg.

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Does selective use of the intra-aortic filter in high-risk cardiac surgical patients lead to better postoperative outcomes?

The objective of this study was to evaluate the effect of an intra-aortic filter on postoperative outcomes in high-risk cardiac surgical patients. An intra-aortic filter was used in 316 (4.9%) of 6442 cardiac surgical cases from 2003 to 2013. A retrospective analysis of the Society of Thoracic Surgeons (STS) registry data was performed for 204 patients with filter placement who underwent coronary artery bypass grafting (CABG) (n = 89), valve replacement (n = 63) or combined CABG and valve replacement (n = 52), matched with 1224 patients without filter placement by STS mortality scores based on propensity scores. Generalized linear modelling was used to compare rates of complications as well as the length of stay and time in the intensive care unit (ICU). A P-value < 0.05 was considered significant. Overall, patients with filters before matching had a significantly higher risk of death than did the patients without filters: 12.0% of patients with filters had an STS mortality risk score ≥4 vs 7.7% of patients without filters (P = 0.027). After analysis of the composite end-point of all STS major morbidities, the matched filter group had fewer overall complications (6.8 vs 13.2%, P = 0.02). The rate of postoperative respiratory failure was lower in the filter group (2.5 vs 7.0%, P = 0.01). Rates of stroke and new-onset haemodialysis, while not statistically different, were almost 50% lower in the filter group. Length of stay in the hospital and in the ICU was not significantly different; however, in patients with postoperative complications, time in the ICU (163 vs 189 h, P = 0.02) was shorter for the filter patients.

The use of the intra-aortic filter reduces postoperative complications after cardiac surgery and should be considered for use in high-risk cases.

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Do cUB domain-containing protein 1 and the epidermal growth factor receptor cooperate to induce cell detachment?

While localized malignancies often respond to available therapies, most disseminated cancers are refractory. Novel approaches, therefore, are needed for the treatment of metastatic disease. CUB domain-containing protein1 (CDCP1) plays an important role in metastasis and drug resistance; the mechanism however, is poorly understood. Breast cancer cell lines were engineered to stably express EGFR, CDCP1 or phosphorylation site mutants of CDCP1. These cell lines were used for immunoblot analysis or affinity purification followed by immunoblot analysis to assess protein phosphorylation and/or protein complex formation with CDCP1. Kinase activity was evaluated using phosphorylation site-specific antibodies and immunoblot analysis in in vitro kinase assays. Protein band excision and mass spectrometry was utilized to further identify proteins complexed with CDCP1 or ΔCDCP1, which is a mimetic of the cleaved form of CDCP1. Cell detachment was assessed using cell counting. This paper reports that CDCP1 forms ternary protein complexes with Src and EGFR, facilitating Src activation and Src-dependent EGFR transactivation. Importantly, we have discovered that a class of compounds termed Disulfide bond Disrupting Agents (DDAs) blocks CDCP1/EGFR/Src ternary complex formation and downstream signaling. CDCP1 and EGFR cooperate to induce detachment of breast cancer cells from the substratum and to disrupt adherens junctions. Analysis of CDCP1-containing complexes using proteomics techniques reveals that CDCP1 associates with several proteins involved in cell adhesion, including adherens junction and desmosomal cadherins, and cytoskeletal elements.

Together, these results suggest that CDCP1 may facilitate loss of adhesion by promoting activation of EGFR and Src at sites of cell-cell and cell-substratum contact.

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Do essential amino acid ratios and mTOR affect lipogenic gene networks and miRNA expression in bovine mammary epithelial cells?

The objective of this study was to study how changing the ratio of Lys to Thr, Lys to His, and Lys to Val affects the expression of lipogenic genes and microRNA (miRNA) in bovine mammary epithelial cells. Triplicate cultures with the respective "optimal" amino acid (AA) ratio (OPAA = Lys:Met 2.9:1; Thr:Phe 1.05:1; Lys:Thr 1.8:1; Lys:His 2.38:1; Lys:Val 1.23:1) plus rapamycin (OPAARMC; positive control), OPAA, Lys:Thr 2.1:1 (LT2.1), Lys:Thr 1.3:1 (LT1.3), Lys:His 3.05:1 (LH3.0), or Lys:Val 1.62:1 (LV1.6) were incubated in lactogenic medium for 12 h. The expression of 15 lipogenic genes and 7 miRNA were evaluated. Responses to LT2.1, LT1.3, LH3.0, and LV1.6 relative to the control (OPAARMC) included up-regulated expression of ACSS2, FABP3, ACACA, FASN, SCD, LPIN1, INSIG1, SREBF1, PPARD, and NR1H3 (commonly known as LXR-α). Furthermore, LV1.6 up-regulated expression of ACSL1, DGAT1, and RXRA and down-regulated PPARG expression. Although no effect of OPAA on expression of PPARG was observed, compared with the control, OPAA up-regulated expression of the PPAR targets ACSS2, FABP3, ACACA, FASN, SCD, LPIN1, INSIG1, and SREBF1. Compared with the control, the expression of the anti-lipogenic MIR27AB was down-regulated by OPAA, LT2.1, LT1.3 and LH3.0. In contrast, compared with the control, the expression of the pro-lipogenic MIR21 was up-regulated by LT2.1, LT1.3, LH3.0, and LV1.6.

The observed up-regulation of lipogenic gene networks and the changes in expression of key miRNA involved in the control of lipogenic balance are indicative of a potentially important role of EAA ratios and mTOR signaling in the regulation of milk fat synthesis.

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Does transcription Factor KLF5 bound a Cyclin E1 Polymorphic Intronic Enhancer to Confer Increased Bladder Cancer Risk?

It is well established that environmental toxins, such as exposure to arsenic, are risk factors in the development of urinary bladder cancer, yet recent genome-wide association studies (GWAS) provide compelling evidence that there is a strong genetic component associated with disease predisposition. A single-nucleotide polymorphism (SNP), rs8102137, was identified on chromosome 19q12, residing 6 kb upstream of the important cell-cycle regulator and proto-oncogene, Cyclin E1 (CCNE1). However, the functional role of this variant in bladder cancer predisposition has been unclear because it lies within a non-coding region of the genome. Here, it is demonstrated that bladder cancer cells heterozygous for this SNP exhibit biased allelic expression of CCNE1 with 1.5-fold more transcription occurring from the risk allele. Furthermore, using chromatin immunoprecipitation assays, a novel enhancer element was identified within the first intron of CCNE1 that binds Kruppel-like Factor 5 (KLF5), a known transcriptional activator in bladder cancer. Moreover, the data reveal that the presence of rs200996365, a SNP in high-linkage disequilibrium with rs8102137 residing in the center of a KLF5 motif, alters KLF5 binding to this genomic region. Through luciferase assays and CRISPR-Cas9 genome editing, a novel polymorphic intronic regulatory element controlling CCNE1 transcription is characterized. These studies uncover how a cancer-associated polymorphism mechanistically contributes to an increased predisposition for bladder cancer development.

A polymorphic KLF5 binding site near the CCNE1 gene explains genetic risk identified through GWAS. Mol Cancer Res; 14(11); 1078-86. ©2016 AACR.

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Does cXCL13 inhibit microRNA-23a through PI3K/AKT signaling pathway in adipose tissue derived-mesenchymal stem cells?

Adipose tissue derived-mesenchymal stem cells (AMSCs) are one of the most widely used MSCs in the cell therapy for regenerative medicine. In the current study, the role of CXCL13 in AMSCs and its potential signaling pathway were investigated. AMSCs were isolated from adipose tissue of healthy subjects. After administrating the cells with CXCL13, the expression levels of miR-23a and runt-related transcription factor 2 (Runx2) were assessed by real-time PCR and western blot. The alterations of phosphoinositide-3 kinase (PI3K)/Akt, stress-activated protein kinase (SAPK)/c-jun kinase (JNK), and extracellular-signal-regulated kinase (ERK1/2) pathways were also evaluated. CXCL13 down-regulated miR-23a and up-regulated Runx2 expression in AMSCs. The inhibitor specific for PI3K/AKT, but not SAPK/JNK and ERK ERK1/2, reversed the effects of CXCL13 on miR-23a and Runx2 expression.

CXCL13 inhibits miR-23a expression through modulating PI3K/AKT pathway in AMSCs.

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Does a Selective Cell Population From Dermis strengthen Bone Regeneration?

: Finding appropriate seed cells for bone tissue engineering remains a significant challenge. Considering that skin is the largest organ, we hypothesized that human bone morphogenetic protein receptor type IB (BmprIB)+ dermal cells could have enhanced osteogenic capacity in the healing of critical-sized calvarial defects in an immunodeficient mouse model. In this study, immunohistochemical staining revealed that BmprIB was expressed throughout reticular dermal cells; the positive expression rate of BmprIB was 3.5% ± 0.4% in freshly separated dermal cells, by flow cytometry. Furthermore, in vitro osteogenic capacity of BmprIB+ cells was confirmed by osteogenic-related staining and marker gene expression compared with unsorted dermal cells. In vivo osteogenic capacity was demonstrated by implantation of human BmprIB+ cell/coral constructs in the treatment of 4-mm diameter calvarial defects in an immunodeficient mouse model compared with implantation of unsorted cell/coral constructs and coral scaffold alone. These results indicate that the selective cell population BmprIB from human dermis is a promising osteogenic progenitor cell that can be a large-quantity and high-quality cell source for bone tissue engineering and regeneration.

Dermal cells are a promising cell population for bone regeneration; unfortunately, the osteogenic potential of unsorted cells was quite low. This study demonstrated that a specific cell population in human dermis-bone morphogenetic protein receptor IB (BmprIB)+ cells-exhibited significantly higher osteogenic potential than unsorted dermal cells by repairing critical-sized calvarial defects in an immunodeficient mouse model. This animal study is an extension of a previous in vitro finding in which BmprIB was proven as a marker for enrichment of osteogenic precursor-like cells in human dermis, indicating that the selective cell population BmprIB from human dermis is a promising osteogenic progenitor cell that can provide a large-quantity and high-quality cell source for bone tissue engineering.

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Do smokers exhibit biased neural processing of smoking and affective images?

There has been growing interest in the role that implicit processing of drug cues can play in motivating drug use behavior. However, the extent to which drug cue processing biases relate to the processing biases exhibited to other types of evocative stimuli is largely unknown. The goal of the present study was to determine how the implicit cognitive processing of smoking cues relates to the processing of affective cues using a novel paradigm. Smokers (n = 50) and nonsmokers (n = 38) completed a picture-viewing task, in which participants were presented with a series of smoking, pleasant, unpleasant, and neutral images while engaging in a distractor task designed to direct controlled resources away from conscious processing of image content. Electroencephalogram recordings were obtained throughout the task for extraction of event-related potentials (ERPs). Smokers exhibited differential processing of smoking cues across 3 different ERP indices compared with nonsmokers. Comparable effects were found for pleasant cues on 2 of these indices. Late cognitive processing of smoking and pleasant cues was associated with nicotine dependence and cigarette use.

Results suggest that cognitive biases may extend across classes of stimuli among smokers. This raises important questions about the fundamental meaning of cognitive biases, and suggests the need to consider generalized cognitive biases in theories of drug use behavior and interventions based on cognitive bias modification. (PsycINFO Database Record

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Are self-reported and automatic cognitions associated with exercise behavior in cancer survivors?

Physical activity is beneficial for cancer survivors, but exercise participation is low in this population. It is therefore important to understand the psychological factors underlying exercise uptake so that more effective interventions can be developed. Social-cognitive theory constructs such as outcome expectancies predict exercise behavior, but self-report measures have several limitations. We examined the associations between implicit (automatic) cognitions and exercise behavior and self-efficacy in endometrial cancer survivors. This was a longitudinal study to examine predictors of exercise behavior in female endometrial cancer survivors who all received an exercise intervention. Participants (N = 100, mean age of 57.0) completed questionnaires to assess self-report exercise-related measures (outcome expectancy and attitudes about and identification with exercise) and reaction time (RT) tasks to assess implicit exercise cognitions (expectancy accessibility, implicit attitudes about exercise, and implicit self-identification with exercise) at baseline and at 2, 4, and 6 months at follow-up. Exercise behavior was measured using accelerometers and self-report. Data were analyzed using linear mixed models. Expectancy accessibility was associated with exercise duration independent of the corresponding self-report measure. Exercise implicit attitudes and self-identification were prospectively associated with exercise self-efficacy only after adjustment for the corresponding self-report measures and baseline self-efficacy. Self-report measures were also associated with study outcomes.

Both self-reported cognitions and implicit cognitions may be useful to identify individuals at risk of failing to exercise. Individuals so identified might be provided with a different or more intensive intervention. The data also suggest cognitive targets for intervention. (PsycINFO Database Record

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Does global transcriptional analysis suggest Lasiodiplodia theobromae pathogenicity factors involved in modulation of grapevine defensive response?

Lasiodiplodia theobromae is a fungus of the Botryosphaeriaceae that causes grapevine vascular disease, especially in regions with hot climates. Fungi in this group often remain latent within their host and become virulent under abiotic stress. Transcriptional regulation analysis of L. theobromae exposed to heat stress (HS) was first carried out in vitro in the presence of grapevine wood (GW) to identify potential pathogenicity genes that were later evaluated for in planta expression. A total of 19,860 de novo assembled transcripts were obtained, forty-nine per cent of which showed homology to the Botryosphaeriaceae fungi, Neofusicoccum parvum or Macrophomina phaseolina. Three hundred ninety-nine have homology with genes involved in pathogenic processes and several belonged to expanded gene families in others fungal grapevine vascular pathogens. Gene expression analysis showed changes in fungal metabolism of phenolic compounds; where genes encoding for enzymes, with the ability to degrade salicylic acid (SA) and plant phenylpropanoid precursors, were up-regulated during in vitro HS response, in the presence of GW. These results suggest that the fungal L-tyrosine catabolism pathway could help the fungus to remove phenylpropanoid precursors thereby evading the host defense response. The in planta up-regulation of salicylate hydroxylase, intradiol ring cleavage dioxygenase and fumarylacetoacetase encoding genes, further supported this hypothesis. Those genes were even more up-regulated in HS-stressed plants, suggesting that fungus takes advantage of the increased phenylpropanoid precursors produced under stress. Pectate lyase was up-regulated while a putative amylase was down-regulated in planta, this could be associated with an intercellular growth strategy during the first stages of colonization.

L. theobromae transcriptome was established and validated. Its usefulness was demonstrated through the identification of genes expressed during the infection process. Our results support the hypothesis that heat stress facilitates fungal colonization, because of the fungus ability to use the phenylpropanoid precursors and SA, both compounds known to control host defense.

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Are differences in dural penetration of clival chordomas associated with different prognosis and expression of platelet-derived growth factor receptor-β?

To compare prognosis of clival chordomas with different dural penetration, and establish the relationship between dural penetration and platelet-derived growth factor receptor (PDGFR)-β signaling pathway. Tumors in Type I (33 cases) showed limited dural penetration, while those in Type II (34 cases) had more serious dural penetration. Cox multivariate regression analysis was used to analyze risk factors affecting survival. Kaplan-Meier analysis measured overall survival (OS) and progression-free survival (PFS). To determine relationship between dural penetration and PDGFR-β signaling, expression of PDGFR-β, Akt, mammalian target of rapamycin (mTOR), and phosphatase and tensin homolog (PTEN) expression was compared using immunohistochemistry, quantitative reverse transcription polymerase chain reaction, and western blotting. Total resection was achieved in nine cases in Type I and eleven in Type II. There were significant correlations between OS and dural penetration (P=0.032) and age (P=0.034). PFS correlated significantly with dural penetration (P=0.022), gender (P=0.001), and degree of resection (P=0.001). Mean OS in Type I was significantly longer than in Type II (P=0.046). Patients aged <55 years had longer OS than those aged ≥55 years (P=0.004). Total resection was correlated with longer PFS (P=0.011). Among patients with tumor totally resected, mean PFS in Type I was significantly longer than in Type II (P=0.007). Expression of PDGFR-β in Type II was higher than in Type I.

Clival chordomas have different degrees of dural penetration. Patients with chordomas with serious dural penetration have poorer prognosis. Higher expression of PDGFR-β is related to more serious dural penetration of clival chordomas.

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Are copy-number variations enriched for neurodevelopmental genes in children with developmental coordination disorder?

Developmental coordination disorder is a common neurodevelopment disorder that frequently co-occurs with other neurodevelopmental disorders including attention-deficit hyperactivity disorder (ADHD). Copy-number variations (CNVs) have been implicated in a number of neurodevelopmental and psychiatric disorders; however, the proportion of heritability in developmental coordination disorder (DCD) attributed to CNVs has not been explored. This study aims to investigate how CNVs may contribute to the genetic architecture of DCD. CNV analysis was performed on 82 extensively phenotyped Canadian children with DCD, with or without co-occurring ADHD and/or reading disorder, and 2988 healthy European controls using identical genome-wide SNP microarrays and CNV calling algorithms. An increased rate of large and rare genic CNVs (p=0.009) was detected, and there was an enrichment of duplications spanning brain-expressed genes (p=0.039) and genes previously implicated in other neurodevelopmental disorders (p=0.043). Genes and loci of particular interest in this group included: GAP43, RBFOX1, PTPRN2, SHANK3, 16p11.2 and distal 22q11.2. Although no recurrent CNVs were identified, 26% of DCD cases, where sample availability permitted segregation analysis, were found to have a de novo rare CNV. Of the inherited CNVs, 64% were from a parent who also had a neurodevelopmental disorder.

These findings suggest that there may be shared susceptibility genes for DCD and other neurodevelopmental disorders and highlight the need for thorough phenotyping when investigating the genetics of neurodevelopmental disorders. Furthermore, these data provide compelling evidence supporting a genetic basis for DCD, and further implicate rare CNVs in the aetiology of neurodevelopmental disorders.

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Do spontaneous ripples in the hippocampus correlate with epileptogenicity and not memory function in patients with refractory epilepsy?

High-frequency oscillations (HFOs, 80-500Hz) are newly-described EEG markers of epileptogenicity. The proportion of physiological and pathological HFOs is unclear, as frequency analysis is insufficient for separating the two types of events. For instance, ripples (80-250Hz) also occur physiologically during memory consolidation processes in medial temporal lobe structures. We investigated the correlation between HFO rates and memory performance. Patients investigated with bilateral medial temporal electrodes and an intellectual capacity allowing for memory testing were included. High-frequency oscillations were visually marked, and rates of HFOs were calculated for each channel during slow-wave sleep. Patients underwent three verbal and three nonverbal memory tests. They were grouped into severe impairment, some impairment, mostly intact, or intact for verbal and nonverbal memory. We calculated a Pearson correlation between HFO rates in the hippocampi and the memory category and compared HFO rates in each hippocampus with the corresponding (verbal - left, nonverbal - right) memory result using Wilcoxon rank-sum test. Twenty patients were included; ten had bilateral, five had unilateral, and five had no memory impairment. Unilateral memory impairment was verbal in one patient and nonverbal in four. There was no correlation between HFO rates and memory performance in seizure onset areas. There was, however, a significant negative correlation between the overall memory performance and ripple rates (r=-0.50, p=0.03) outside the seizure onset zone.

Our results suggest that the majority of spontaneous hippocampal ripples, as defined in the present study, may reflect pathological activity, taking into account the association with memory impairment. The absence of negative correlation between memory performance and HFO rates in seizure onset areas could be explained by HFO rates in the SOZ being generally so high that differences between areas with remaining and impaired memory function cannot be seen.

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Does mineralocorticoid Receptor Blockade improve Insulin Sensitivity in the Rat Heart and a Possible Molecular Mechanism?

Extensive research has explored the role of aldosterone in insulin resistance. Recent evidence suggests that the mineralocorticoid receptor (MR) mediates aldosterone-induced dysregulation of cytokines, and most of this research has focused on adjustments in fat tissue and adipocytes. However, the direct effect of MR blockade on insulin resistance in cardiomyocytes remains largely unknown. In the present study, we investigated whether MR blockade improves insulin-sensitizing factors in insulin-resistant rats and attenuates the dysregulation of the aldosterone-related transport of adiponectin and glucose in cardiomyocytes and examined the underlying mechanisms. The effects of aldosterone, MR inhibitors (e.g., eplerenone), a peroxisome proliferator-activated receptor (PPAR) α agonist, and a p38 mitogen-activated protein kinase (MAPK) inhibitor on adiponectin and glucose transport were studied at the mRNA and protein levels in vitro and in vivo. Our data revealed that aldosterone reduced the expression of adiponectin and inhibited the transport of glucose in cardiomyocytes and that MR blockade reversed these affects. In vivo, MR blockade improved insulin-sensitive parameters and increased adiponectin expression in the myocardia of high-fat diet rats. Furthermore, aldosterone promoted p38MAPK expression but negatively affected PPARα expression, and the downregulation of adiponectin by aldosterone was reversed by MR blockade, a PPARα agonist, and a p38 MAPK inhibitor.

The above results suggested that aldosterone promoted insulin resistance in the heart and that this effect could be partly reversed by MR blockade through signal transduction in the P38 MAPK pathway and PPARα.

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Do birth order and hospitalization for alcohol and narcotics use in Sweden?

Previous studies have shown that birth order is an important predictor of later life health as well as socioeconomic attainment. In this study, we examine the relationship between birth order and hospitalization for alcohol and narcotics use in Sweden. We study the relationship between birth order and hospitalization related to alcohol and narcotics use before and after the age of 20 using Swedish register data for cohorts born 1987-1994. We apply Cox proportional hazard models and use sibling fixed effects, eliminating confounding by factors shared by the siblings. Before age 20 we find that later born siblings are hospitalized for alcohol use at a higher rate than first-borns, and there is a monotonic increase in the hazard of hospitalization with increasing birth order. Second-borns are hospitalized at a rate 47% higher than first-borns, and third-borns at a rate 65% higher. Similar patterns are observed for hospitalization for narcotics use. After age 20 the pattern is similar, but the association is weaker. These patterns are consistent across various sibling group sizes.

Later born siblings are more likely to be hospitalized for both alcohol and narcotics use in Sweden. These birth order effects are substantial in size, and larger than the estimated sex differences for the risk of hospitalization related to alcohol and drug use before age 20, and previous estimates for socioeconomic status differences in alcohol and drug abuse.

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Is discrete Pathophysiology Uncommon in Patients with Nonspecific Arm Pain?

Nonspecific symptoms are common in all areas of medicine. Patients and caregivers can be frustrated when an illness cannot be reduced to a discrete pathophysiological process that corresponds with the symptoms. We therefore asked the following questions: 1) Which demographic factors and psychological comorbidities are associated with change from an initial diagnosis of nonspecific arm pain to eventual identification of discrete pathophysiology that corresponds with symptoms? 2) What is the percentage of patients eventually diagnosed with discrete pathophysiology, what are those pathologies, and do they account for the symptoms? We evaluated 634 patients with an isolated diagnosis of nonspecific upper extremity pain to see if discrete pathophysiology was diagnosed on subsequent visits to the same hand surgeon, a different hand surgeon, or any physician within our health system for the same pain. There were too few patients with discrete pathophysiology at follow-up to address the primary study question. Definite discrete pathophysiology that corresponded with the symptoms was identified in subsequent evaluations by the index surgeon in one patient (0.16% of all patients) and cured with surgery (nodular fasciitis). Subsequent doctors identified possible discrete pathophysiology in one patient and speculative pathophysiology in four patients and the index surgeon identified possible discrete pathophysiology in four patients, but the five discrete diagnoses accounted for only a fraction of the symptoms.

Nonspecific diagnoses are not harmful. Prospective randomized research is merited to determine if nonspecific, descriptive diagnoses are better for patients than specific diagnoses that imply pathophysiology in the absence of discrete verifiable pathophysiology.

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States diet quality , risk factors and access to care among low-income uninsured American adults in states expanding Medicaid vs. expanding under the affordable care act?

The Affordable Care Act (ACA) Medicaid expansion varies in availability across states. We compared characteristics of low-income uninsured residents in both Medicaid nonexpanding and expanding states with respect to their dietary quality, health risk factors, and access to care. Data from the 2007-2012 National Health and Nutrition Examination Survey was matched with the Kaiser Family Foundation Medicaid expansion data. Bivariate and multivariate regressions were estimated to assess differences across expanding and non-expanding states. The non-expansion group had a lower Healthy Eating Index score (41.8 vs. 44.1, p-value=0.006), a higher Body Mass Index (29.9 vs. 28.9, p-value=0.032), higher obesity prevalence (41% vs. 33%, p-value=0.007), and lower asthma prevalence (14.8% vs. 19.7%, p-value=0.037) compared with the expansion group.

Differences across states in Medicaid coverage under the ACA may lead to widening disparities in health outcomes between expanding and non-expanding states.

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Does jAK2 inhibitor combined with DC-activated AFP-specific T-cells enhance antitumor function in a Fas/FasL signal-independent pathway?

Combination therapy for cancer is more effective than using only standard chemo- or radiotherapy. Our previous results showed that dendritic cell-activated α-fetoprotein (AFP)-specific T-cells inhibit tumor in vitro and in vivo. In this study, we focused on antitumor function of CD8(+) T-cells combined with or without JAK2 inhibitor. Proliferation and cell cycle were analyzed by CCK-8 and flow cytometry. Western blot was used to analyze the expression level of related protein and signaling pathway. We demonstrated reduced viability and induction of apoptosis of tumor cells with combination treatment. Intriguingly, cell cycle was blocked at the G1 phase by using AFP-specific CD8(+) T-cells combined with JAK2 inhibitor (AG490). Furthermore, an enhanced expression of BAX but no influence on Fas/FasL was detected from the tumor cells.

These results indicate a Fas/FasL-independent pathway for cellular apoptosis in cancer therapies with the treatment of AFP-specific CD8(+) T-cells combined with JAK2 inhibitor.

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Does intrathecal synthesis of anti-Hu antibodies distinguish patients with paraneoplastic peripheral neuropathy and encephalitis?

Paraneoplastic syndromes are serious immune caused diseases of the peripheral and/or central nervous system associated with malignant neoplasm. Symptoms develop when antibodies against antigens expressed by tumor cells cross-react with neuronal proteins. Antineuronal antibodies are usually examined in patient's sera while examination of the cerebrospinal fluid (CSF) often fails. Furthermore, the few previous reports describing CSF data summarized different antineuronal antibodies and/or regarded patients with different neurological symptoms as one group. We retrospectively evaluated data of 18 patients with paraneoplastic syndromes due to anti-Hu antibodies. The study aimed to differentiate patients with peripheral neuropathy and encephalitis by cerebrospinal fluid (CSF) parameters including anti-Hu antibody titers. Our results confirm previous observations that serum titers of anti-Hu antibodies and standard CSF values do not differ between patients with neuropathy and encephalitis. However, analysis of CSF anti-Hu titers and calculating the intrathecal synthesis helped to discriminate between both groups.

In conclusion, our results indicate that patients even with one defined antineuronal antibody need to be regarded separately depending on the involved location of the nervous system. We recommend incorporation of anti-Hu analyses in the CSF and calculating the intrathecal synthesis in patients with anti-Hu syndrome.

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Is an anterior left ventricular lead position associated with increased mortality and non-response in cardiac resynchronization therapy?

Non-response to cardiac resynchronization therapy (CRT) might be due to insufficient resynchronization as a result of a sub-optimal left ventricular lead positon (LV-LP). To evaluate the impact of different LV-LPs on mortality and symptomatic improvement in a large cohort of patients treated with CRT. We performed a nationwide cohort study on consecutive patients receiving a CRT device from 1997 to 2012 registered in the Danish pacemaker and ICD register. The LV-LP was defined clockwise in a left anterior oblique (LAO) view and categorized as anterior (≤2 o'clock), lateral (2 to 4 o'clock) or posterior (>4 o'clock), and as basal, mid-ventricular, or apical in a right anterior oblique (RAO) view. Outcomes were all cause mortality and clinical response (improvement in NYHA class). Adjusted hazard ratio (aHR) and odds ratio (aOR) with 95% confidence intervals (CI) were calculated using Cox and logistic regression analysis. A total of 2594 patients were included. A lateral LV-LP, (aHR 0.77, 95% CI 0.64-0.92, p=0.004), and a posterior LV-LP, (aHR 0.71 95% CI 0.53-0.97, p=0.029) were associated with lower mortality as compared to an anterior LV-LP. A lateral LV-PV was associated with higher clinical response rate as compared to an anterior LV-LP (aOR 1.37, 1.03-1.83, p=0.032). No statistically significant associations were observed between LV-LP in the RAO view and mortality or clinical response.

An anterior left ventricular lead position is associated with increased all-cause mortality and lower clinical response rate in patients treated with CRT and should be avoided.

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Are white matter hyperintensities more highly associated with preclinical Alzheimer 's disease than imaging and cognitive markers of neurodegeneration?

Cognitive tests and nonamyloid imaging biomarkers do not consistently identify preclinical AD. The objective of this study was to evaluate whether white matter hyperintensity (WMH) volume, a cerebrovascular disease marker, is more associated with preclinical AD than conventional AD biomarkers and cognitive tests. Elderly controls enrolled in the Alzheimer's Disease Neuroimaging Initiative (ADNI, n = 158) underwent florbetapir-PET scans, psychometric testing, neuroimaging with MRI and PET, and APOE genetic testing. Elderly controls the Parkinson's progression markers initiative (PPMI, n = 58) had WMH volume, cerebrospinal fluid (CSF) Aβ1-42, and APOE status measured. In the ADNI cohort, only WMH volume and APOE ε4 status were associated with cerebral Aβ (standardized β = 0.44 and 1.25, P = .03 and .002). The association between WMH volume and APOE ε4 status with cerebral Aβ (standardized β = 1.12 and 0.26, P = .048 and .045) was confirmed in the PPMI cohort.

WMH volume is more highly associated with preclinical AD than other AD biomarkers.

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Are plasma lipoprotein ( a ) levels associated with the severity of coronaryheart disease in Han Chinese people?

The aim of this study was to investigate the association of lipoprotein(a) [Lp(a)] with the severity of coronary heart disease (CHD) in Han Chinese people. Six hundred and seventy-nine patients with angiographically defined CHD were enrolled in this cross-sectional study. Fasting lipids were measured, and the severity of CHD was quantitatively assessed for each patient according to the number of stenotic coronary branches and the Gensini scoring system. The levels of Lp(a), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), very low-density lipoprotein cholesterol (VLDL-C), and apolipoprotein (apo) B100 increased, while high-density lipoprotein cholesterol (HDL-C) and apoAI decreased significantly with the number of stenotic vessels. The levels of Lp(a) increased and HDL-C and apoAI decreased significantly with the Gensini scores. The logistic regression analyses showed that Lp(a) and HDL-C were independently associated with the number of stenotic coronary vessels after adjusting for age, weight, body mass index, sex, smoking, alcohol consumption, hypertension, diabetes, triglycerides, TC, LDL-C, VLDL-C, apoAI, and apoB100. However, only Lp(a) was independently associated with the Gensini scores after adjustment.

Our data indicate that Lp(a) might be a useful marker in predicting the severity of coronary heart disease.

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Does rectal or intramuscular diclofenac reduce the incidence of pancreatitis afterendoscopic retrograde cholangiopancreatography?

Acute pancreatitis is the most common adverse event of endoscopic retrograde cholangiopancreatography (ERCP). We aimed to evaluate the efficacy of intramuscular diclofenac sodium for prophylaxis of post-ERCP pancreatitis (PEP) in comparison to the rectal form. One hundred and fifty consecutive patients who underwent ERCP were enrolled in this single-center, prospective, randomized controlled study. Patients were randomized into three groups. The first group received 75 mg of diclofenac sodium via intramuscular route and the second group received 100 mg of diclofenac sodium rectally 30-90 min before the procedure. The third group served as the control group. Patients were evaluated for post-ERCP pancreatitis with serum amylase levels and abdominal pain 24 h after the procedure. The overall incidence of PEP was 6% (n = 9) and 2% (n = 1) in the intramuscular (IM) and rectal groups, respectively, and 14% in the control group (P = 0.014). Nineteen (12.7%) patients developed post-ERCP abdominal pain (8% in IM, 10% in rectal, and 20% in control group; P = 0.154). Twenty-five (16.6%) patients developed post-ERCP hyperamylasemia (10% in IM, 12% in rectal, and 24% in control group; P = 0.03).

Prophylaxis with diclofenac given rectally or intramuscularly is an effective option for the management of post-ERCP pancreatitis.

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Is overexpression of β-Catenin and Cyclin D1 Associated with Poor Overall Survival in Patients with Stage IA-IIA Squamous Cell Lung Cancer Irrespective of Adjuvant Chemotherapy?

This study was aimed at understanding the effect of β-catenin and cyclin D1 on overall survival in patients with early-stage NSCLC and at evaluating if the prognostic effect can be modified by adjuvant chemotherapy. We retrospectively analyzed the expression of β-catenin and cyclin D1 using immunohistochemistry in formalin-fixed paraffin-embedded tissues from 576 patients with early-stage NSCLC. The median duration of follow-up was 5.1 years. Overexpression of β-catenin and cyclin D1 was found in 56% and 50% of 576 cases, respectively. Overexpression of β-catenin and cyclin D1 was significantly associated with poor overall survival (p = 0.003 and p = 0.0009, respectively; log rank test) in squamous cell carcinomas, not in adenocarcinomas. The prognostic significance of each protein in the squamous cell carcinomas was limited to stages IA, IB, and IIA. In addition, simultaneous overexpression of β-catenin and cyclin D1 in the squamous cell carcinomas synergistically increased hazard ratios (HRs) 15.79 (95% confidence interval [CI] = 1.09-51.23; p =0.04) for stage IA, 10.30 (95% CI = 2.29-46.41; p = 0.002) for stage 1B, and 3.55 (95% CI = 1.22-10.36; p = 0.02) times for stage 2A compared to those without overexpression of the two proteins, after adjusting for confounding factors. In addition, the effect was not dependent on adjuvant chemotherapy.

The present study suggests that simultaneous overexpression of β-catenin and cyclin D1 may be associated with poor overall survival irrespective of platinum-based adjuvant chemotherapy in stage IA-IIA squamous cell carcinoma of the lung.

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Does dNA hypomethylation of Synapsin II CpG islands associate with increased gene expression in bipolar disorder and major depression?

The Synapsins (SYN1, SYN2, and SYN3) are important players in the adult brain, given their involvement in synaptic transmission and plasticity, as well as in the developing brain through roles in axon outgrowth and synaptogenesis. We and others previously reported gene expression dysregulation, both as increases and decreases, of Synapsins in mood disorders, but little is known about the regulatory mechanisms leading to these differences. Thus, we proposed to study DNA methylation at theses genes' promoter regions, under the assumption that altered epigenetic marks at key regulatory sites would be the cause of gene expression changes and thus part of the mood disorder etiology. We performed CpG methylation mapping focusing on the three genes' predicted CpG islands using the Sequenom EpiTYPER platform. DNA extracted from post-mortem brain tissue (BA10) from individuals who had lived with bipolar disorder (BD), major depressive disorder (MDD), as well as psychiatrically healthy individuals was used. Differences in methylation across all CpGs within a CpG island and between the three diagnostic groups were assessed by 2-way mixed model analyses of variance. We found no significant results for SYN1 or SYN3, but there was a significant group difference in SYN2 methylation, as well as an overall pattern of hypomethylation across the CpG island. Furthermore, we found a significant inverse correlation of DNA methylation with SYN2a mRNA expression.

These findings contribute to previous work showing dysregulation of Synapsins, particularly SYN2, in mood disorders and improve our understanding of the regulatory mechanisms that precipitate these changes likely leading to the BD or MDD phenotype.

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Does upright posture improve affect and fatigue in people with depressive symptoms?

Slumped posture is a diagnostic feature of depression. While research shows upright posture improves self-esteem and mood in healthy samples, little research has investigated this in depressed samples. This study aimed to investigate whether changing posture could reduce negative affect and fatigue in people with mild to moderate depression undergoing a stressful task. Sixty-one community participants who screened positive for mild to moderate depression were recruited into a study purportedly on the effects of physiotherapy tape on cognitive function. They were randomized to sit with usual posture or upright posture and physiotherapy tape was applied. Participants completed the Trier Social Stress Test speech task. Changes in affect and fatigue were assessed. The words spoken by the participants during their speeches were analysed. At baseline, all participants had significantly more slumped posture than normative data. The postural manipulation significantly improved posture and increased high arousal positive affect and fatigue compared to usual posture. The upright group spoke significantly more words than the usual posture group, used fewer first person singular personal pronouns, but more sadness words. Upright shoulder angle was associated with lower negative affect and lower anxiety across both groups.

The experiment was only brief and a non-clinical sample was used.

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Does simvastatin attenuate Acute Lung Injury Via Regulating Cdc42-PAK4 and Endothelial Microparticles?

Simvastatin has lung vascular-protective effects via augmentation of endothelial barrier function. Accordingly, on the basis of our previous study, we hypothesized that endothelial cell (EC) protection by simvastatin is dependent on the stabilization on cytoskeletons. Sixty C57BL/6 mice were divided into two experimental groups: LPS group (L group) and LPS+simvastatin treated group (L+S group). All mice in these two groups received an intraperitoneal injection of LPS (10 mg/kg/d). Simvastatin was administered intraperitoneally immediately after the LPS injection in animals of the L+S group at a dose of 20 mg/kg/day. Lung injury degree and the protective effects of simvastatin against LPS-induced lung injury were assessed at the time-points of 24, 48 and 72 h post-injection. Serum alanine transaminase (ALT), serum creatinine (Scr) were identified to assess the hepatic and renal side-effects of simvastatin. LPS inhibited the cytoskeletal regulating proteins of Cdc42 and PAK4, and was accompanied by an increased circulating endothelial microparticles (EMPs) level. The adherent junction (AJ) protein of VE-cadherin was also decreased by LPS, and was accompanied by a thickening alveolar wall, increased lung W/D values and high albumin concentration in bronchoalveolar lavage (BAL). Protective effects of simvastatin against LPS-induced lung injury were illustrated by regulating and stabilizing cytoskeletons, as well as intercellular AJs. The values of ALT and Scr were all lower than the common upper limits according to assay kits.

An increased serous EMP level associated with Cdc42-PAK4 can be deemed as a useful pulmonary injury marker in LPS-treated mice, and our results might be more relevant in guiding the clinical treatment of ALI by intervening Cdc42-PAK4 or EMPs.

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Does rpoE promote invasion and intracellular survival by regulating SPI-1 and SPI-2 in Salmonella enterica serovar Typhi?

To demonstrate the role of RpoE during the later stage of hyperosmotic stress in Salmonella. Expressions of SPI-1 and SPI-2 under hyperosmotic stress for 120 min were investigated by a microarray, and the invasion and intracellular survival of wild-type and ΔrpoE strains were compared. The global differential expression of bacterial proteins between the wild-type and ΔrpoE strains was examined after 120 min of hyperosmotic stress. SPI-1 and SPI-2 were repressed, and the invasion and intracellular survival were defected in the ΔrpoE strain. Thirteen bacterial-associated proteins and 11 secreted proteins differed significantly between the wild-type and ΔrpoE strains.

RpoE may promote invasion and intracellular survival by regulating the expression of SPI-1 and SPI-2.

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Is minor neurological dysfunction in five year old very preterm children associated with lower processing speed?

Minor neurological dysfunction (MND) is present in one quarter to one third of children born very preterm (VP). The more severe form, complex (c)-MND has been associated with learning disabilities, behavioural and motor problems. To study the association between c-MND and neurocognitive and motor disabilities at age five in VP children without CP. Ninety-four children born with gestational age<30weeks and/or a birth weight<1000g were assessed at five years corrected age. MND was classified according to Touwen. The Wechsler Preschool and Primary School Scale of Intelligence (WPPSI-III-NL) was used to measure intelligence. Simple reaction time, focused attention and visuomotor coordination were measured using the Amsterdam Neuropsychological Tasks, and working memory using a Digit Span Task. For motor skills the Movement Assessment Battery for children (M-ABC2) was used. Eighty-one percent was classified as 'normal' (no or simple (s-)-MND) and 19% as 'abnormal'(c-MND or mild CP). The abnormal group had a significantly lower processing speed quotient (PSQ), M-ABC percentile score and slower simple Reaction Time than the normal group. Verbal IQ, Performance IQ, working memory, focused attention and visuomotor coordination did not differ between groups. Exclusion of the mild CP cases (n=4) led to similar results.

Five year old VP children with c-MND have lower PSQ, slower reaction time, and poorer motor skills, than those without c-MND. Neurological examination should include identification of MND to help identify children at risk for neurocognitive disabilities.

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Does engineering high Zn in tomato shoot through expression of AtHMA4 involves tissue-specific modification of endogenous genes?

To increase the Zn level in shoots, AtHMA4 was ectopically expressed in tomato under the constitutive CaMV 35S promoter. However, the Zn concentration in the shoots of transgenic plants failed to increase at all tested Zn levels in the medium. Modification of Zn root/shoot distribution in tomato expressing 35S::AtHMA4 depended on the concentration of Zn in the medium, thus indicating involvement of unknown endogenous metal-homeostasis mechanisms. To determine these mechanisms, those metal-homeostasis genes that were expressed differently in transgenic and wild-type plants were identified by microarray and RT-qPCR analysis using laser-assisted microdissected RNA isolated from two root sectors: (epidermis + cortex and stele), and leaf sectors (upper epidermis + palisade parenchyma and lower epidermis + spongy parenchyma). Zn-supply-dependent modification of Zn root/shoot distribution in AtHMA4-tomato (increase at 5 μM Zn, no change at 0.5 μM Zn) involved tissue-specific, distinct from that in the wild type, expression of tomato endogenous genes. First, it is suggested that an ethylene-dependent pathway underlies the detected changes in Zn root/shoot partitioning, as it was induced in transgenic plants in a distinct way depending on Zn exposure. Upon exposure to 5 or 0.5 μM Zn, in the epidermis + cortex of the transgenics' roots the expression of the Strategy I Fe-uptake system (ethylene-dependent LeIRT1 and LeFER) was respectively lower or higher than in the wild type and was accompanied by respectively lower or higher expression of the identified ethylene genes (LeNR, LeACO4, LeACO5) and of LeChln. Second, the contribution of LeNRAMP2 expression in the stele is shown to be distinct for wild-type and transgenic plants at both Zn exposures. Ethylene was also suggested as an important factor in a pathway induced in the leaves of transgenic plants by high Zn in the apoplast, which results in the initiation of loading of the excess Zn into the mesophyll of "Zn accumulating cells".

In transgenic tomato plants, the export activity of ectopically expressed AtHMA4 changes the cellular Zn status, which induces coordinated tissue-specific responses of endogenous ethylene-related genes and metal transporters. These changes constitute an important mechanism involved in the generation of the metal-related phenotype of transgenic tomato expressing AtHMA4.

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Is recurrent dilatation in resistant benign esophageal strictures : timing significant?

Benign esophageal strictures are frequently encountered pathologies occurring due to various reasons. Repeated dilatations may be needed, particularly in resistant strictures. This study aimed to evaluate patients who underwent repeated dilatations in our clinic due to resistant esophageal strictures. Sixteen patients who underwent multiple dilatations in our clinic with the diagnosis of resistant benign esophageal stricture between 2007 and 2014 were studied for age, sex, etiology, symptoms, complications, number of dilatations, and intervals between dilatations. Under general anesthesia, all patients underwent dilatation with Savary-Gilliard bougie dilators with the help of rigid esophagoscopy. In 10 of the patients, stenosis was cervical, and in others it was in the thoracic esophagus. The mean dilatation performance was 4.4 (range: 3-12). In 9 patients, dilatations were performed when the patients presented with the complaint of dysphagia. Following the initial dilatation performed for dysphagia, 7 patients underwent endoscopy and dilatation 3-5 times with 1-week intervals without waiting for the development of dysphagia symptoms. These patients developed no complications, and no stenting was needed. In 5 patients, restenosis developed despite multiple dilatations, and esophageal stent placement was performed.

Dilatations performed at frequent intervals without waiting for the symptoms of dysphagia can contribute to safer and more effective results in resistant benign esophageal strictures.

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Is a persistently low HBV DNA level a predictor of spontaneous HBsAg clearance in patients with chronic hepatitis B?

The incidence and predictors of spontaneous hepatitis B surface-antigen (HBsAg) seroclearance in patients with chronic hepatitis B virus (HBV) were evaluated. A total of 1427 patients with chronic HBV infection, who were followed between 1994 and 2013, were investigated in this retrospective study. All data were extracted from patient files. Spontaneous HBsAg seroclearance occurred in 84 patients during 8798 person-years of follow-up. The patients were categorized into 3 groups at follow-up based on HBV DNA features as continuously <100 copies/mL (Group A), 0-10,000 copies/mL (Group B), and 0 to >10,000 copies/mL (Group C). Alanine aminotransferase features in the 2 groups were categorized as continuously normal (<40 U/L) and 0 to >40 U/L. Spontaneous HBsAg seroclearance was seen primarily in patients with Group A HBV DNA features, and continuously low HBV DNA values were the main predictor of HBsAg seroclearance (P < 0.001).

These results suggest that a continuously low viral load is the most important factor affecting spontaneous HBsAg seroclearance.

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Are verbal memory and search speed in early midlife associated with mortality over 25 years ' follow-up , independently of health status and early life factors : a British birth cohort study?

Cognitive capabilities in childhood and in late life are inversely associated with mortality rates. However, it is unclear if adult cognition, at a time still relatively free from comorbidity, is associated with subsequent mortality, and whether this explains the associations of early life factors with adult mortality. We used data from the MRC National Survey of Health and Development, a birth cohort study prospectively assessing 5362 participants born in 1946. The present analysis includes participants followed up from age 43 and undergoing cognitive assessment (verbal memory and search speed). Mortality outcomes were notified through linkage with a national register. Cox regression was used to estimate mortality hazards in relation to cognitive performance at age 43, adjusting for early life factors, socioeconomic position and health status. Data were available on 3192 individuals. Univariable analyses indicated that adult verbal memory and search speed, parental factors, childhood cognition and educational attainment were associated with mortality. However, multivariable models showed that the mortality associations with earlier life factors were explained by adult cognitive capability. A standard deviation increase in verbal memory and search speed scores was associated with lower mortality rates [hazard ratio (HR) = 0.86, 95% confidence interval (CI) 0.77-0.97, P = 0.02; HR = 0.88, 95% CI 0.78-1.00, P = 0.05, respectively), after adjustment for adult health.

Cognitive capability in early midlife was inversely associated with mortality rates over 25 years and accounted for the associations of family background, childhood cognitive ability and educational attainment with mortality. These findings, in a nationally representative cohort with long-term follow-up, suggest that building cognitive reserve may improve later life health and survival chances.

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Is vonoprazan superior to proton pump inhibitors in healing artificial ulcers of the stomach post-endoscopic submucosal dissection : A propensity score-matching analysis?

Proton pump inhibitors (PPI) are effective at healing artificial ulcers after endoscopic submucosal dissection (ESD) for gastric neoplasms; however, the efficacy of vonoprazan is not completely understood. The aim of the present study was to determine the healing effect of vonoprazan on artificial ulcers post-gastric ESD relative to PPI. Thirty-five patients who underwent gastric ESD between April and November 2015 were treated with vonoprazan 20 mg/day for 4 weeks and subsequently underwent endoscopy for evaluation of ulcer size (V group). Ulcer contraction rate was determined by the following formula: ([ESD specimen size] - [ulcer size at 4 weeks after ESD])/(ESD specimen size) × 100%. We compared the results with those of a historical control group treated with esomeprazole 20 mg/day for 4 weeks after gastric ESD and subsequently measured their ulcer size (33 patients, E group) by propensity score-matching methods. Sixty-two subjects were enrolled after propensity score-matching. Ulcer contraction rate at 4 weeks after ESD in the V group was significantly higher than that of the E group (97.7 ± 3.2% vs 94.5 ± 6.7%, respectively, P = 0.025). Number of subjects with a scar-stage ulcer (100% contraction rate) tended to be higher in the V group relative to the E group (32% [10 of 31] vs 13% [4 of 31], respectively, P = 0.070, McNemar's chi-squared test).

Vonoprazan has a faster post-gastric ESD artificial ulcer contraction rate than esomeprazole. Vonoprazan may supersede PPI in treating post-ESD artificial ulcers of the stomach.

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Does hIF-2α Expression regulate Sprout Formation into 3D Fibrin Matrices in Prolonged Hypoxia in Human Microvascular Endothelial Cells?

During short-term hypoxia, Hypoxia Inducible Factors (particular their subunits HIF-1α and HIF-2α) regulate the expression of many genes including the potent angiogenesis stimulator VEGF. However, in some pathological conditions chronic hypoxia occurs and is accompanied by reduced angiogenesis. We investigated the effect of prolonged hypoxia on the proliferation and sprouting ability of human microvascular endothelial cells and the involvement of the HIFs and Dll4/Notch signaling. Human microvascular endothelial cells (hMVECs), cultured at 20% oxygen for 14 days and seeded on top of 3D fibrin matrices, formed sprouts when stimulated with VEGF-A/TNFα. In contrast, hMVECs precultured at 1% oxygen for 14 days were viable and proliferative, but did not form sprouts into fibrin upon VEGF-A/TNFα stimulation at 1% oxygen. Silencing of HIF-2α with si-RNA partially restored the inhibition of endothelial sprouting, whereas HIF-1α or HIF-3α by si-RNA had no effect. No involvement of Dll4/Notch pathway in the inhibitory effect on endothelial sprouting by prolonged hypoxia was found. In addition, hypoxia decreased the production of urokinase-type plasminogen activator (uPA), needed for migration and invasion, without a significant effect on its inhibitor PAI-1. This was independent of HIF-2α, as si-HIF-2α did not counteract uPA reduction.

Prolonged culturing of hMVECs at 1% oxygen inhibited endothelial sprouting into fibrin. Two independent mechanisms contribute. Silencing of HIF-2α with si-RNA partially restored the inhibition of endothelial sprouting pointing to a HIF-2α-dependent mechanism. In addition, reduction of uPA contributed to reduced endothelial tube formation in a fibrin matrix during prolonged hypoxia.

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Is nR5A1 a novel disease gene for 46 , XX testicular and ovotesticular disorders of sex development?

We aimed to identify the genetic cause in a cohort of 11 unrelated cases and two sisters with 46,XX SRY-negative (ovo)testicular disorders of sex development (DSD). Whole-exome sequencing (n = 9), targeted resequencing (n = 4), and haplotyping were performed. Immunohistochemistry of sex-specific markers was performed on patients' gonads. The consequences of mutation were investigated using luciferase assays, localization studies, and RNA-seq. We identified a novel heterozygous NR5A1 mutation, c.274C>T p.(Arg92Trp), in three unrelated patients. The Arg92 residue is highly conserved and located in the Ftz-F1 region, probably involved in DNA-binding specificity and stability. There were no consistent changes in transcriptional activation or subcellular localization. Transcriptomics in patient-derived lymphocytes showed upregulation of MAMLD1, a direct NR5A1 target previously associated with 46,XY DSD. In gonads of affected individuals, ovarian FOXL2 and testicular SRY-independent SOX9 expression observed.

We propose NR5A1, previously associated with 46,XY DSD and 46,XX primary ovarian insufficiency, as a novel gene for 46,XX (ovo)testicular DSD. We hypothesize that p.(Arg92Trp) results in decreased inhibition of the male developmental pathway through downregulation of female antitestis genes, thereby tipping the balance toward testicular differentiation in 46,XX individuals. In conclusion, our study supports a role for NR5A1 in testis differentiation in the XX gonad.Genet Med advance online publication 04 August 2016Genetics in Medicine (2016); doi:10.1038/gim.2016.118.

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Does the QuickLine IL-6 lateral flow immunoassay improve the rapid intraoperative diagnosis of suspected periprosthetic joint infections?

When deciding upon the best treatment strategy in revision arthroplasty, it is absolutely crucial to use the best possible preoperative detection whether a periprosthetic joint infection (PJI) is present or not. New molecular markers investigated in serum samples and synovial fluid can help to improve the preoperative diagnosis. In 2001, a novel IL-6 lateral flow immunoassay testing device was introduced which has never been tested in synovial fluid so far. For our study we investigated whether the test can be used safely, feasibly and time effectively with synovial fluid gathered from potentially infected THAs or TKAs and whether the already published cutoff for IL-6 in synovial fluid predicting a PJI can be reproduced using the QuickLine IL-6 immunoassay. After ethic approval and within the scope of a prospective controlled trial we investigated 26 patients (m = 9, 34.6%; f= 17, 65.4%) with n = 13 (50%) potentially infected total hip arthroplasties (THAs) and n = 13 (50%) suspected PJIs of total knee arthroplasties (TKAs). Sterile aspirated synovial fluid was examined for total leukocyte count and cell differentiation by a blood count analyzer in body fluid mode as well as for IL-6 (Immulite, Siemens Medical Solutions Diagnostics GmbH, Eschborn, Germany). Another part of the joint aspirate was tested using the QuickLine IL-6 Test by Milenia Biotec (Milenia Biotec, Gießen, Germany). The mean concentration of IL-6 as determined from our reference laboratory testing (Siemens Immulight) for aseptic cases was 1,219 pg/mL (SD 1,369 pg/mL, min 134 pg/mL-max 4,214 pg/mL). The mean IL-6 concentration measured via the IL-6 QuickLine for aseptic cases was 410 pg/mL (SD 371 pg/mL, min 100 pg/mL-max 1562 pg/mL). The test showed no false negative or false positive results in the cases tested. In six patients, PJI was considered proven. The QuickLine Test indicated IL 6 concentrations > 10,000 pg/mL in these cases without further quantification above this maximum detection threshold. Results from the QuickLine Test and the laboratory tests were matched and a non-linear best fit curve (log-log-curve) was applied. The subsequent Spearman correlation showed a correlation coefficient of r = 0.92 (95% CI 0.81-0.97) which corresponds to a two-tailed p-value of < 0.0001, respectively. As a primary finding we were able to show that the Milenia QuickLine IL-6 Test can be used safely, feasibly and time effectively with synovial fluid gathered intraoperatively from potentially infected THAs or TKAs. The test as provided worked well in 84.6% of the samples tested and failed only due to very viscous synovial fluid. As a secondary result we found that the previously published cut-off for IL-6 in synovial fluid predicting a PJI with a sensitivity of 46.88% and a specificity of 97.62% can be reproduced using the QuickLine IL-6 immunoassay.

Taking the limitations of the low sample size as a given this relatively simple point of care (POC) assay showed promising results in our pilot trial and may help diagnosing PJI. It may help physicians and surgeons to choose the best and least invasive treatment strategy for patients presenting with painful arthroplasty.

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Does a Randomized Trial of Expanding Choice set to Motivate Advance Directive Completion?

Evidence suggests that advance directives may improve end-of-life care among seriously ill patients, but improving completion rates remains a challenge. This study tested the influence of increasing the number of options for completing an advance directive among seriously ill patients. Outpatients (N = 316) receiving hemodialysis across 15 dialysis centers in the Philadelphia region between July 2014 and July 2015 were randomized to receive either the option to complete a brief advance directive form or expanded options including a brief, expanded, or comprehensive form. Patients in both groups could decline to complete an advance directive or take their selected version home. The primary outcome was a returned, completed advance directive. Secondary outcomes included whether patients wanted to complete an advance directive, decision satisfaction, quality of life at 3 months, and patient factors associated with advance directive completion. Although offering more advance directive options was not significantly associated with increased rates of completion (13.1% in the standard group v. 12.2% in the expanded group, P = 0.80), it did significantly increase the proportion of patients who wanted to complete an advance directive and took one home (71.9% in standard v. 85.3% in expanded, P = 0.004). There was no difference in satisfaction (P = 0.65) or change in quality of life between groups (P = 0.63). A higher baseline quality of life was independently associated with advance directive completion (P = 0.006).

These results suggest that although an expanded choice set may initially nudge patients toward completing advance directives without restricting choice, increasing actual completion requires additional interventions that overcome downstream barriers.

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Does race predict the development of metastases in men with nonmetastatic castration-resistant prostate cancer?

Although race is associated with prostate cancer progression in early stage disease, once men have advanced disease, it is unclear whether race continues to predict a poor outcome. The authors hypothesized that, in an equal-access setting among patients with castration-resistant prostate cancer (CRPC) and no known metastases (M0/Mx), black men would receive imaging tests at similar rates as nonblack men (ie, there would be an equal opportunity to detect metastases) but would have a higher risk of metastatic disease. In total, 837 men who were diagnosed with M0/Mx CRPC during 2000 through 2014 from 5 Veterans Affairs hospitals in the SEARCH (Shared Equal Access Regional Cancer Hospital) database were analyzed. Data on all imaging tests after CRPC diagnosis were collected, including date, type, and outcome. Multivariable Cox models were used to test associations between race and the time to first metastasis, first bone metastasis, first bone scan, second bone scan among men who had a negative first bone scan, and overall survival. Black men (n = 306) were equally as likely as nonblack men (n = 531) to receive a first and second bone scan after a diagnosis of CRPC. There were no significant differences in the risk of developing any metastases, bone metastases, time to bone scans, or overall survival between black men and nonblack men (all P > .2).

The lack of racial differences in the development of metastases and scanning practices observed in this study suggests that, once men have a diagnosis of M0/Mx CRPC, race may not be a prognostic factor. Efforts to understand prostate cancer racial disparities may derive greater benefit by focusing on the risk of developing prostate cancer and on the outcomes of men who have early stage disease. Cancer 2016;122:3848-3855. © 2016 American Cancer Society.

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Does dyschloremia be a Risk Factor for the Development of Acute Kidney Injury in Critically Ill Patients?

Dyschloremia is common in critically ill patients, although its impact has not been well studied. We investigated the epidemiology of dyschloremia and its associations with the incidence of acute kidney injury and other intensive care unit outcomes. This is a single-center, retrospective cohort study at Mayo Clinic Hospital-Rochester. All adult patients admitted to intensive care units from January 1st, 2006, through December 30th, 2012 were included. Patients with known acute kidney injury and chronic kidney disease stage 5 before intensive care unit admission were excluded. We evaluated the association of dyschloremia with ICU outcomes, after adjustments for the effect of age, gender, Charlson comorbidity index and severity of illness score. A total of 6,025 patients were enrolled in the final analysis following the implementation of eligibility criteria. From the cohort, 1,970 patients (33%) developed acute kidney injury. Of the total patients enrolled, 4,174 had a baseline serum chloride. In this group, 1,530 (37%) had hypochloremia, and 257 (6%) were hyperchloremic. The incidence of acute kidney injury was higher in hypochloremic and hyperchloremic patients compared to those with a normal serum chloride level (43% vs.30% and 34% vs. 30%, respectively; P < .001). Baseline serum chloride was lower in the acute kidney injury group vs. the non-acute kidney injury group [100 mmol/L (96-104) vs. 102 mmol/L (98-105), P < .0001]. In a multivariable logistic regression model, baseline serum chloride of ≤94 mmol/L found to be independently associated with the risk of acute kidney injury (OR 1.7, 95% CI 1.1-2.6; P = .01).

Dyschloremia is common in critically ill patients, and severe hypochloremia is independently associated with an increased risk of development of acute kidney injury.

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Does ginsenoside Rd attenuate DNA Damage by Increasing Expression of DNA Glycosylase Endonuclease VIII-like Proteins after Focal Cerebral Ischemia?

Ginsenoside Rd (GSRd), one of the main active ingredients in traditional Chinese herbal Panax ginseng, has been found to have therapeutic effects on ischemic stroke. However, the molecular mechanisms of GSRd's neuroprotective function remain unclear. Ischemic stroke-induced oxidative stress results in DNA damage, which triggers cell death and contributes to poor prognosis. Oxidative DNA damage is primarily processed by the base excision repair (BER) pathway. Three of the five major DNA glycosylases that initiate the BER pathway in the event of DNA damage from oxidation are the endonuclease VIII-like (NEIL) proteins. This study aimed to investigate the effect of GSRd on the expression of DNA glycosylases NEILs in a rat model of focal cerebral ischemia. NEIL expression patterns were evaluated by quantitative real-time polymerase chain reaction in both normal and middle cerebral artery occlusion (MCAO) rat models. Survival rate and Zea-Longa neurological scores were used to assess the effect of GSRd administration on MCAO rats. Mitochondrial DNA (mtDNA) and nuclear DNA (nDNA) damages were evaluated by the way of real-time analysis of mutation frequency. NEIL expressions were measured in both messenger RNA (mRNA) and protein levels by quantitative polymerase chain reaction and Western blotting analysis. Apoptosis level was quantitated by the expression of cleaved caspase-3 and terminal deoxynucleotidyl transferase-mediated dUTP biotin nick end labeling assay. We found that GSRd administration reduced mtDNA and nDNA damages, which contributed to an improvement in survival rate and neurological function; significantly up-regulated NEIL1 and NEIL3 expressions in both mRNA and protein levels of MCAO rats; and reduced cell apoptosis and the expression of cleaved caspase-3 in rats at 7 days after MCAO.

Our results indicated that the neuroprotective function of GSRd for acute ischemic stroke might be partially explained by the up-regulation of NEIL1 and NEIL3 expressions.

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Is miR-103a targeting Piezo1 involved in acute myocardial infarction through regulating endothelium function?

Acute myocardial infarction (AMI) is commonly known as the heart attack. The molecular events involved in the development of AMI remain unclear. This study was to investigate the expression of miR-103a in patients with high blood pressure (HBP) and AMI patients with and without HBP, as well as its effect on endothelial cell functions. MiR-103a expression in plasma and peripheral blood mononuclear cells was measured by real-time polymerase chain reaction (PCR). The regulatory effect of miR-103a on Piezo1 gene was identified by a luciferase reporter system. The role of miR-103a in endothelial cells was evaluated by the capillary tube formation ability and cell viability of human umbilical vein endothelial cells (HUVECs). The plasma miR-103a concentration was significantly elevated in patients with HBP alone, AMI alone, and comorbidity of AMI and HBP. The miR-103a expression in peripheral blood mononuclear cells (PBMCs) in patients with AMI and HBP was significantly higher than the one in healthy controls (p < 0.05), however miR-103a expression in PBMCs was not significantly different among patients with HBP alone, patients with AMI alone, and healthy controls. MiR-103a targeted Piezo1 and inhibited Piezo1 protein expression, which subsequently reduced capillary tube formation ability and cell viability of HUVECs.

MiR-103a might be a potential biomarker of myocardium infarction and could be used as an index for the diagnosis of AMI. It may be involved in the development of high blood pressure and onset of AMI through regulating the Piezo1 expression.

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Does high-Speed Cycling Intervention improve Rate-Dependent Mobility in Older Adults?

The aim was to determine the feasibility of a six-week speed-based exercise program that could be used to initiate new exercise behaviors and improve rapid movement in older adults approaching frailty. The intervention group included 14 older adults (3 males, 11 females, mean (SD) age: 70 (7.6) years, height: 1.6 (.11) m, mass: 76.8 (12.0) kg, BMI: 27.7(4.7)). The control group included 12 older adults (6 males, 6 females, mean (SD) age: 69.2 (6.9) years, height: 1.7 (.09) m, mass: 78.2 (10.9) kg, BMI: 25.3 (2.7)). Subjects included active older adults, including regular exercisers, but none were engaged in sports or exercises with an emphasis on speed (e.g. cycling spin classes or tennis). Stationary recumbent cycling was selected to minimize fall risk and low pedaling resistance reduced musculoskeletal and cardiovascular load. Two weekly 30-minute exercise sessions consisted of interval training in which subjects pedaled at preferred cadence and performed ten 20-s fast cadence intervals separated by 40-s of active recovery at preferred cadence. Significant Group by Time interactions (p<.05) supported a 2-s improvement in the timed up and go test and a 34% improvement in rapid isometric knee extension contractions in the exercise group but not in controls. Central neural adaptations are suggested because this lower extremity exercise program also elicited significant improvements in the untrained upper extremities of the exercise group (elbow extension RFD-SF and 9-Hole Peg Test, p<.05).

These results demonstrate that a relatively low dose of speed-based exercise can improve neuromuscular function and tests of mobility in older adults. Such a program serves as a sensible precursor to subsequent, more vigorous training or as an adjunct to a program where a velocity emphasis is lacking.

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Does suPAR predict Cardiovascular Events and Mortality in Patients With Asymptomatic Aortic Stenosis?

Soluble urokinase plasminogen activator receptor (suPAR) is an inflammatory marker associated with subclinical cardiovascular damage and cardiovascular events. Whether suPAR is of prognostic value in asymptomatic patients with aortic stenosis (AS) remains unknown. Plasma suPAR levels were measured in 1503 patients with a mean age of 68 years who were recruited in the Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) study. Cox regression analysis was performed to evaluate associations between suPAR and the composite end points of ischemic cardiovascular events (ICEs), aortic valve events (AVEs), cardiovascular and all-cause mortality after adjusting for traditional cardiovascular risk factors, and allocation to treatment. The multivariate adjusted hazard ratio (HR) (95% confidence interval [CI]) per unit log2 ng/mL increase in suPAR was HR, 1.5; 95% CI, 1.2-1.9; P = 0.002 for ICEs; HR, 1.2; 95% CI, 0.9-1.5; P = 0.071) for AVEs; HR, 2.0; 95% CI, 1.2-3.3; P = 0.007) for cardiovascular mortality, and HR, 2.0; 95% CI, 1.4-2.9; P < 0.001 for all-cause mortality.

In patients with mild-moderate AS, suPAR is independently associated with the incidence of ICEs, cardiovascular mortality, and all-cause mortality.

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Is tobacco smoking associated with decreased semen quality?

Tobacco smoking is a public health issue and has been implicated in adverse reproductive outcomes including semen quality. Available data however provides conflicting findings. The objective of this study was to evaluate the effect of tobacco smoking on semen quality among men in Ghana. In this study, a total of 140 subjects were recruited, comprising 95 smokers and 45 non-smokers. Smokers were further categorized into mild, moderate and heavy smokers. Semen parameters such as sperm concentration, motility, viability and normal morphology were measured according to the World Health Organisation criteria. The study showed that smokers had significantly lower semen volume, sperm concentration, sperm motility, total sperm count, sperm morphology, free testosterone and follicle stimulating hormone (p <0.05 respectively), compared with non-smokers. Smokers were at a higher risk of developing oligospermia, asthenozoospermia and teratozoospermia (OR = 3.1, 4.2 and, 4.7; p <0.05) than non-smokers.

Results demonstrated a decline in semen quality in a dose dependent tobacco smoking manner.

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Does bmal1 induce osteoblast differentiation via regulation of BMP2 expression in MC3T3-E1 cells?

Mammalian circadian rhythms regulate many metabolic processes. Recent studies suggest that brain and muscle Arnt-like 1 (BMAL1), an important component of mammalian circadian rhythm, is associated with insulin signaling. Several studies have shown that insulin is associated with bone metabolism; however, the relationship between BMAL1 and osteoblasts remains unclear. Expression of osteogenic markers and Bmal1 in MC3T3-E1 cells was measured by RT-PCR and Western blotting. Alizarin red S staining was performed to assess matrix mineralization in MC3T3-E1 cells. mRNA levels of osteogenic genes and Bmal1 were up-regulated in MC3T3-E1 cells upon insulin treatment. In addition, Bmal1 overexpression increased the expression of osteogenic genes including inhibitor of DNA binding (Id1), Runt-related transcription factor 2 (Runx2), and osteocalcin (OC). Interestingly, expression of Bone morphogenetic protein-2 (BMP2), an important upstream factor of Id1, Runx2, and OC, was markedly increased by Bmal1. Finally, we confirmed that insulin-induced BMP2 expression was attenuated in Bmal1 knockout (KO) cells. PCR analysis and alizarin red S staining showed that insulin-mediated increases gene expression and calcium deposition were reduced in Bmal1 KO cells compared to wild-type cells.

Taken together, these results demonstrate that Bmal1 promotes osteoblast differentiation by regulating BMP2 expression in MC3T3-E1 cells.

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Does adherence to Dietary Recommendations for Food Group Intakes be Low in the Mexican Population?

Given the high prevalence of obesity and noncommunicable diseases in Mexico and the key role of dietary quality in these conditions, it is important to determine Mexicans' adherence to dietary recommendations. Our aim was to estimate the percentage of the Mexican population who adhere to dietary recommendations for key food groups. We analyzed 7983 participants aged ≥5 y from the nationally representative Mexican National Health and Nutrition Survey 2012. Dietary intake data were collected by using one 24-h recall and a repeated 24-h recall in 9% of the sample. We used the National Cancer Institute method for episodically consumed foods, which uses a 2-part (probability and amount) mixed regression model to estimate the usual intake distribution and its association with sociodemographic variables. For the food groups that are encouraged, only 1-4% of the population (range across sex and age groups) reached the recommended intake of legumes, 4-8% for seafood, 7-16% for fruit and vegetables, and 9-23% for dairy. For food groups that are discouraged, only 10-22% did not exceed the recommended upper limit for sugar-sweetened beverages, 14-42% for high saturated fat and/or added sugar (HSFAS) products, and 9-50% for processed meats, whereas the majority (77-93%) did not exceed the limit for red meat. A lower proportion of adolescents than children and adults adhered to recommendations for several food groups. Participants with higher socioeconomic status (SES) and living in urban areas consumed more (probability of consuming and/or amount consumed) fruit and vegetables, dairy, and HSFAS products, but they consumed fewer legumes than those of lower SES and living in rural areas.

These results reveal the poor dietary quality of the Mexican population and the urgent need to shift these habits. If current intakes continue, the burden of disease due to obesity and noncommunicable chronic diseases will likely remain elevated in the Mexican population.

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Is simultaneous CT angiography and whole-body CT an effective imaging approach before multiorgan retrieval?

To assess the role of whole-body computed tomography (CT) for determining morphological suitability before multiorgan retrieval (MOR) in brain dead patients. Fifty-one clinically brain dead patients (21 women, 30 men; mean age 61 year±15) were included in this prospective, single center study. All patients had CT angiography of the brain and whole-body CT examination. CT images were evaluated for the presence of morphological abnormalities of lungs, liver and other abdominal organs and presence of vascular anatomical variants. The results of CT examinations were compared to intraoperative findings observed during organ harvesting and/or the results of histopathological analysis of biopsy specimens. The impact of whole-body CT examination on the harvesting process was evaluated. Ninety-five percent of vascular anatomical variants that were found intraoperatively were depicted on CT. CT density measurements predicted surgical finding of steatosis in 80% of patients. Whole-body CT changed the MOR strategy in 21/51 patients (41%) including 3 MOR cancellations and 8 grafts refusals, whereas organ harvesting was continued in 10 patients after histopathological analysis was performed.

Selection of potential graft donors using whole-body CT is reliable and improves graft selection during MOR.

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Does comparative study of the failure rates among 3 implantable defibrillator lead?

After the introduction of the Biotronik Linox S/SD high-voltage lead, several cases of early failure have been observed. The purpose of this article was to assess the performance of the Linox S/SD lead in comparison to 2 other contemporary leads. We used the prospective Erasmus MC ICD registry to identify all implanted Linox S/SD (n = 408), Durata (St. Jude Medical, model 7122) (n = 340), and Endotak Reliance (Boston Scientific, models 0155, 0138, and 0158) (n = 343) leads. Lead failure was defined by low- or high-voltage impedance, failure to capture, sense or defibrillate, or the presence of nonphysiological signals not due to external interference. During a median follow-up of 5.1 years, 24 Linox (5.9%), 5 Endotak (1.5%), and 5 Durata (1.5%) leads failed. At 5-year follow-up, the cumulative failure rate of Linox leads (6.4%) was higher than that of Endotak (0.4%; P < .0001) and Durata (2.0%; P = .003) leads. The incidence rate was higher in Linox leads (1.3 per 100 patient-years) than in Endotak and Durata leads (0.2 and 0.3 per 100 patient-years, respectively; P < .001). A log-log analysis of the cumulative hazard for Linox leads functioning at 3-year follow-up revealed a stable failure rate of 3% per year. The majority of failures consisted of noise (62.5%) and abnormal impedance (33.3%).

This study demonstrates a higher failure rate of Linox S/SD high-voltage leads compared to contemporary leads. Although the mechanism of lead failure is unclear, the majority presents with abnormal electrical parameters. Comprehensive monitoring of Linox S/SD high-voltage leads includes remote monitoring to facilitate early detection of lead failure.

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Does environment shape the fecal microbiome of invasive carp species?

Although the common, silver, and bighead carps are native and sparsely distributed in Eurasia, these fish have become abundant and invasive in North America. An understanding of the biology of these species may provide insights into sustainable control methods. The animal-associated microbiome plays an important role in host health. Characterization of the carp microbiome and the factors that affect its composition is an important step toward understanding the biology and interrelationships between these species and their environments. We compared the fecal microbiomes of common, silver, and bighead carps from wild and laboratory environments using Illumina sequencing of bacterial 16S ribosomal RNA (rRNA). The fecal bacterial communities of fish were diverse, with Shannon indices ranging from 2.3 to 4.5. The phyla Proteobacteria, Firmicutes, and Fusobacteria dominated carp guts, comprising 76.7 % of total reads. Environment played a large role in shaping fecal microbial community composition, and microbiomes among captive fishes were more similar than among wild fishes. Although differences among wild fishes could be attributed to feeding preferences, diet did not strongly affect microbial community structure in laboratory-housed fishes. Comparison of wild- and lab-invasive carps revealed five shared OTUs that comprised approximately 40 % of the core fecal microbiome.

The environment is a dominant factor shaping the fecal bacterial communities of invasive carps. Captivity alters the microbiome community structure relative to wild fish, while species differences are pronounced within habitats. Despite the absence of a true stomach, invasive carp species exhibited a core microbiota that warrants future study.

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Does the Decline of Amylase Level of Pancreatic Juice After Pancreaticoduodenectomy predict Postoperative Pancreatic Fistula?

Postoperative pancreatic fistula (POPF) is a life-threatening complication after pancreaticoduodenectomy (PD). The aim of this study is to evaluate the significance of pancreatic amylase level of pancreatic juice for PF after PD. The subjects were 46 patients who underwent PD between January 2012 and August 2015 at Jikei University Hospital. We retrospectively investigated the relation between patient characteristics including pancreatic amylase level of pancreatic juice through the pancreatic drainage tube and the incidence of POPF (grade B or grade C according to the International Study Group on the Pancreatic Fistula) using univariate and multivariate analyses. The decline of pancreatic amylase level of pancreatic juice was evaluated by 1 - postoperative day 3/postoperative day 1 ratio. In univariate analysis, nonductal adenocarcinoma (P = 0.0252), soft pancreatic remnant (P = 0.0155), and decline of pancreatic amylase level of pancreatic juice ≥ 80% (P = 0.0010) were significant predictors of POPF. In multivariate analysis, decline of pancreatic amylase level of pancreatic juice of 80% or greater (P = 0.0192) was the only significant independent parameter.

Decline of pancreatic amylase level of pancreatic juice can predict POPF after PD.

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Is pretreatment quality-of-life score a better discriminator of oesophageal cancer survival than performance status?

Performance status [Eastern Cooperative Oncology Group (ECOG)] is a physician-assigned score indicating a patient's fitness for treatment. Functional assessment of cancer therapy-esophagus (FACT-E) is a patient-reported, health-related quality-of-life (HRQOL) instrument containing an oesophageal cancer subscale (ECS). Our objective was to assess the discriminative ability of pretreatment FACT-E and ECS when compared with performance status in predicting survival in patients with Stage II-III oesophageal cancer. Patient data from four prospective studies were pooled together. These four studies included oesophageal patients who received chemoradiation either as neoadjuvant therapy or as definitive therapy. Three separate Cox regressions were performed considering FACT-E, ECS and ECOG as the main predictors, respectively. Receiver-operating characteristics analyses were performed. Of the 120 curative intent patients, 39.8% (n = 51), 58.6% (n = 75) and 1.6% (n = 2) had ECOG 0, 1 and 2, respectively. On Cox regression analysis, pretreatment FACT-E (P = 0.04) and ECS (P = 0.004) but not ECOG (P = 0.27) were independently associated with overall survival. ECOG could not discriminate between survivors and non-survivors (P = 0.28) with an area under the curve (AUC) of 0.56 [95% confidence interval (CI): 0.45-0.66], whereas FACT-E (P = 0.02) and ECS (P < 0.001) were discriminative with AUC = 0.63 (95% CI: 0.52-0.73) and AUC = 0.69 (95% CI: 0.60-0.79), respectively.

In patients with Stage II-III oesophageal cancer being considered for curative therapy, pretreatment FACT-E and ECS have better discrimination for survival than does ECOG. The majority of patients were ECOG 0/1. Thus, these patient-derived scores were able to discriminate survivors from non-survivors even within this constrained range of clinician-assigned performance status. This highlights the potential utility of FACT-E and ECS as prognostic tools.

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Does algorithmic Approach With Clinical Pathology Consultation improve Access to Specialty Care for Patients With Systemic Lupus Erythematosus?

Harris Health System (HHS) is a safety net system providing health care to the underserved of Harris County, Texas. There was a 6-month waiting period for a rheumatologist consult for patients with suspected systemic lupus erythematosus (SLE). The objective of the intervention was to improve access to specialty care. An algorithmic approach to testing for SLE was implemented initially through the HHS referral center. The algorithm was further offered as a "one-click" order for physicians, with automated reflex testing, interpretation, and case triaging by clinical pathology. Data review revealed that prior to the intervention, 80% of patients did not have complete laboratory workups available at the first rheumatology visit. Implementation of algorithmic testing and triaging of referrals by pathologists resulted in decreasing the waiting time for a rheumatologist by 50%.

Clinical pathology intervention and case triaging can improve access to care in a county health care system.

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Does use of Estrogen-Containing Contraception be Associated With Increased Concentrations of 25-Hydroxy Vitamin D?

Small studies suggest exogenous estrogen may improve vitamin D status, but the etiology is unclear because women who use hormones may make lifestyle choices that differentially affect vitamin D status. Our objective was to investigate the association between use of hormonal contraception and 25-hydroxy-vitamin D (25(OH)D). We used linear regression modeling of cross-sectional data to estimate percent change in season-adjusted serum 25(OH)D with estrogen use after adjustment for other factors. At the enrollment clinic visit (2010-2012) into a cohort study of uterine fibroids, each subject provided a blood sample, had anthropomorphic variables and skin reflectance measured, and answered questionnaires on demographics, dietary and supplement intake, contraceptive use, reproductive and medical history, and behaviors. A total of 1662 African American women, community volunteers, 23-34 years old, living in the Detroit, Michigan, area were included. None. Serum 25(OH)D was measured. Serum 25(OH)D concentrations were low (70% <20 ng/ml). Current use of an estrogen-containing contraceptive was associated with a 20% (95% confidence interval: 14-27) increase in 25(OH)D after adjustment. There was no increase in 25(OH)D among participants who had used estrogen in the past, but were not current users, indicating that results were unlikely to be due to unmeasured confounding by factors related to contraceptive choice.

The increase in 25(OH)D with use of estrogen-containing contraceptives raise mechanistic questions regarding the biological pathways involved, and highlights the need for studies that examine possible endogenous estrogen effects on vitamin D.

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Does blood transfusion in preterm infants improve intestinal tissue oxygenation without alteration in blood flow?

The objective of the study was to investigate the splanchnic blood flow velocity and oximetry response to blood transfusion in preterm infants according to postnatal age. Preterm infants receiving blood transfusion were recruited to three groups: 1-7 (group 1; n = 20), 8-28 (group 2; n = 21) and ≥29 days of life (group 3; n = 18). Superior mesenteric artery (SMA) peak systolic (PSV) and diastolic velocities were measured 30-60 min pre- and post-transfusion using Doppler ultrasound scan. Splanchnic tissue haemoglobin index (sTHI), tissue oxygenation index (sTOI) and fractional tissue oxygen extraction (sFTOE) were measured from 15-20 min before to post-transfusion using near-infrared spectroscopy. The mean pretransfusion Hb in group 1, 2 and 3 was 11, 10 and 9 g/dl, respectively. The mean (SD) pretransfusion SMA PSV in group 1, 2 and 3 was 0·63 (0·32), 0·81 (0·33) and 0·97 (0·40) m/s, respectively, and this did not change significantly following transfusion. The mean (SD) pretransfusion sTOI in group 1, 2 and 3 was 36·7 (19·3), 44·6 (10·4) and 41·3 (10·4)%, respectively. The sTHI and sTOI increased (P < 0·01), and sFTOE decreased (P < 0·01) following transfusion in all groups. On multivariate analysis, changes in SMA PSV and sTOI following blood transfusion were not associated with PDA, feeding, pretransfusion Hb and mean blood pressure.

Pretransfusion baseline splanchnic tissue oximetry and blood flow velocity varied with postnatal age. Blood transfusion improved intestinal tissue oxygenation without altering mesenteric blood flow velocity irrespective of postnatal ages.

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Do older people remain on blood pressure agents despite being hypotensive resulting in increased mortality and hospital admission?

the use of antihypertensive medication in older people in order to prevent cardiovascular events is well established. The use of such agents has been encouraged by incentive schemes in the United Kingdom including the Quality and Outcomes Framework. In addition, many guidelines recommend good blood pressure (BP) control in the elderly. However, in older people antihypertensives can cause adverse effects related to hypotension. the aim of this study was to assess the prevalence of low BP and impact on outcomes, particularly in the presence of antihypertensive treatment, in a primary care population of older people. a retrospective observational cohort study in people over the age of 70 years registered with primary care providers in Kent. a total of 11,167 patients over 70 years old were analysed, 6,373 female (57%). Systolic blood pressure (SBP) was below 120 mmHg in 1,297 people (844 on antihypertensives), below 110 mmHg in 474 (313 on antihypertensives) and below 100 mmHg in 128 (89 on antihypertensives). Hypotension was independently associated with mortality, acute kidney injury and hospital admission.

the results demonstrate that low SBP is associated with adverse events, it is possible that the pursuit of BP control at a population level may lead to over-treatment in certain groups of patients. This may result in an increased incidence of adverse events particularly in older people.

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Is decrease of pulmonary blood flow detected by phase contrast MRI correlated with a decrease in lung volume and increase of lung fibrosis area determined by computed tomography in interstitial lung disease?

Lung volume and pulmonary blood flow decrease in patients with interstitial lung disease (ILD). The purpose of this study was to assess the relationship between pulmonary blood flow and lung volume in ILD patients. This research was approved by the institutional review board. Twenty-seven patients (9 men, 18 women; mean age, 59 years; range, 24-79 years) with ILD were included. Blood flow was assessed in the pulmonary trunk and the left and right pulmonary arteries by phase contrast magnetic resonance imaging (MRI). Lung volume and the computed tomography (CT) visual score that indicates the severity of ILD were assessed on the left and right sides by thin-section CT scanning. Lung volume was automatically measured by lung analysis software (VINCENT Ver. 4). The CT visual score was measured by averaging the proportion of abnormal lung area at five anatomic levels. Pearson's correlation coefficient was used to determine the relationship between pulmonary blood flow and lung volume. Pulmonary blood flow showed a significant correlation with lung volume (both: r=0.52, p=0.006; left: r=0.61, p=0.001; right: r=0.54, p=0.004) and CT visual score (both: r=-0.39, p=0.04; left: r=-0.48, p=0.01; right: r=-0.38, p=0.04). Partial correlation analysis, controlled for age, height and weight, showed a significant correlation between pulmonary blood flow and lung volume (both: r=0.43, p=0.03; left: r=0.55, p=0.005; right: r=0.48, p=0.01) and CT visual score (both: r=-0.58, p=0.003; left: r=-0.51, p=0.01; right: r=-0.64, p=0.001).

In ILD, reduced pulmonary blood flow is associated with reduced lung volume and increased abnormal lung area.

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Does one-stage Revision With Catheter Infusion of Intraarticular Antibiotics Successfully treat Infected THA?

Two-stage revision surgery for infected total hip arthroplasty (THA) is commonly advocated, but substantial morbidity and expense are associated with this technique. In certain cases of infected THA, treatment with one-stage revision surgery and intraarticular infusion of antibiotics may offer a reasonable alternative with the distinct advantage of providing a means of delivering the drug in high concentrations. We describe a protocol for intraarticular delivery of antibiotics to the hip through an indwelling catheter combined with one-stage revision surgery and examine (1) the success as judged by eradication of infection at 1 year when treating chronically infected cemented stems; (2) success in treating late-onset acute infections in well-ingrown cementless stems; and (3) what complications were associated with this approach in a small case series. Between January 2002 and July 2013, 30 patients (30 hips) presented to the senior author for treatment of infected THA. Of those, 21 patients (21 hips) with infected cemented THAs underwent débridement and single-stage revision to cementless total hip implants followed by catheter infusion of intraarticular antibiotics. Nine patients (nine hips) with late-onset acute infections in cementless THA had bone-ingrown implants. These patients were all more than 2 years from their original surgery and had acute symptoms of infection for 4 to 9 days. Seven had their original THA elsewhere, and two were the author's patients. All were symptom-free until the onset of their infection, and none had postoperative wound complications, fever, or prolonged pain suggestive of a more chronic process. They were treated with débridement and head and liner exchange, again followed by catheter infusion of intraarticular antibiotics. During this time period, this represented all infected THAs treated by the senior author, and all were treated with this protocol; no patient underwent two-stage exchange during this time, and no patients were lost to followup. At the time of the surgery, two Hickman catheters were placed in each hip to begin intraarticular delivery of antibiotics in the early postoperative period. Antibiotics were infused daily into the hip for 6 weeks with the tubes used for infusion only. Eleven of the single-stage revisions and four of the hips treated with débridement had methicillin-resistant Staphylococcus aureus. Patients were considered free of infection if they had no clinical signs of infection and had a normal C-reactive protein and erythrocyte sedimentation rate at 1 year. Complications were ascertained by chart review. Twenty of 21 (95%) infections in patients who had single-stage revision for chronically infected cemented THA were apparently free from infection and remained so at a mean followup of 63 months (range, 25-157 months). One case grew Candida albicans in the operative cultures and remained free of signs of infection after rerevision followed by infusion of fluconazole. The nine cementless THAs treated with débridement and head/liner exchange all remained free of signs of infection at a mean followup of 74 months (range, 62-121 months). Few complications were associated with the technique. Four patients had elevated serum levels of vancomycin without renal function changes and two patients had transient blood urea nitrogen/creatinine elevations with normal vancomycin levels that resolved with dosage adjustments. No patient had evidence of permanent renal damage. None of the patients in this study developed a chronic fistula or had significant drainage from the catheter site.

Single-stage revision for chronically infected cemented THA and débridement of bone-ingrown cementless THA with late-onset acute infection followed with indwelling catheter antibiotic infusion can result in infection eradication even when resistant organisms are involved. Larger study groups would better assess this technique and prospective comparisons to more traditional one- and two-stage revision techniques for infected THA will likely require multi-institutional approaches.

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Is breslow density a novel prognostic feature in cutaneous malignant melanoma?

In 1970, Breslow described his eponymously named thickness measurement. No-one has sought to enhance the Breslow thickness (BT). The aim of this study was to demonstrate a proof of concept that the density of melanoma cells at the position where the BT is measured is a morphological prognostic biomarker, which we name the Breslow density (BD). The hypothesis was that the BD has prognostic value for overall survival (OS) and is independent of the BT. We analysed 100 cutaneous melanomas, and followed REMARK guidelines. The BD was the estimated percentage dermal area occupied by melanoma cells in a specified location. The BT and BD had a strong correlation (P = 2.1 × 10

We show a proof of concept that the BD represents a novel morphological prognostic biomarker that is independent of the BT, and that there is potential to combine these into a Breslow score. Larger studies are needed to validate the BD, but the simplicity of this biomarker makes it a strong candidate for translation to clinical practice.

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Is survival associated with complete response on MRI after neoadjuvant chemotherapy in ER-positive HER2-negative breast cancer?

Pathological complete remission (pCR) of estrogen receptor (ER)-positive/human epidermal growth factor receptor 2 (HER2)-negative breast cancer is rarely achieved after neoadjuvant chemotherapy (NAC). In addition, the prognostic value of pCR for this breast cancer subtype is limited. We explored whether response evaluation by magnetic resonance imaging (MRI) is associated with recurrence-free survival after NAC in ER-positive/HER2-negative breast cancer. MRI examinations were performed in 272 women with ER-positive/HER2-negative breast cancer before, during and after NAC. MRI interpretation included lesion morphology at baseline, changes in morphology and size, and contrast uptake kinetics. These MRI features, clinical characteristics and final pathology were correlated with recurrence-free survival. The median follow up time was 41 months. There were 35 women with events, including 19 breast-cancer-related deaths. On multivariable analysis, age younger than 50 years (hazard ratio (HR) = 2.55, 95 % confidence interval (CI) 1.3, 5.02, p = 0.007), radiological complete response after NAC (HR = 14.11, CI 1.81, 1818; p = 0.006) and smaller diameters of washout/plateau enhancement at MRI after NAC (HR = 1.02, CI 1.00, 1.04, p = 0.036) were independently associated with best recurrence-free survival. Pathological response was not significant; HR = 2.12, CI 0.86, 4.64, p = 0.096.

MRI after NAC in ER-positive/HER2-negative tumors may be predictive of recurrence-free survival. A radiological complete response at MRI after NAC is associated with an excellent prognosis.

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Does early identification of sepsis in hospital inpatients by ward nurses increase 30-day survival?

Systemic inflammatory response syndrome (SIRS) and sepsis are now frequently identified by observations of vital signs and detection of organ failure during triage in the emergency room. However, there is less focus on the effect on patient outcome with better observation and treatment at the ward level. This was a before-and-after intervention study in one emergency and community hospital within the Mid-Norway Sepsis Study catchment area. All patients with confirmed bloodstream infection have been prospectively registered continuously since 1994. Severity of sepsis, observation frequency of vital signs, treatment data, length of stay (LOS) in high dependency and intensive care units, and mortality were retrospectively registered from the patients' medical journals. The post-intervention group (n = 409) were observed better and had higher odds of surviving 30 days (OR 2.7, 95 % CI 1.6, 4.6), lower probability of developing severe organ failure (0.7, 95 % CI 0.4, 0.9), and on average, 3.7 days (95 % CI 1.5, 5.9 days) shorter LOS than the pre-intervention group (n = 472).

In a cohort with stable mortality rates, early sepsis recognition by ward nurses may have reduced progression of disease and improved survival for patients in hospital with sepsis.

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Does casein glycomacropeptide-derived peptide IPPKKNQDKTE ameliorate high glucose-induced insulin resistance in HepG2 cells via activation of AMPK signaling?

Recently, casein glycomacropeptide (GMP)-derived peptide was found to possess potent antioxidant and anti-inflammatory activities. In this study, the improvement effects and underlying molecular mechanisms of GMP-derived peptide on hepatic insulin resistance were investigated. The peptide IPPKKNQDKTE was identified from GMP papain hydrolysates by LC-ESI-MS/MS. Effects of IPPKKNQDKTE on glucose metabolism and expression levels of the hepatic insulin signaling proteins in high glucose-induced insulin-resistant HepG2 cells were evaluated. Results showed that IPPKKNQDKTE dose-dependently increased glucose uptake and intracellular glycogen in insulin-resistant HepG2 cells without affecting cell viability. IPPKKNQDKTE increased the phosphorylation of Akt and GSK3β and decreased the expression levels of p-GS, G6Pase and PEPCK. These IPPKKNQDKTE-mediated protection effects were reversed by PI3K/Akt inhibitor LY294002, showing the mediatory role of PI3K/Akt. Moreover, treatment with IPPKKNQDKTE reduced IRS-1 Ser307 phosphorylation and increased phosphorylation of AMPK. Knockdown AMPK using siRNA in HepG2 cells increased Ser307 phosphorylation of IRS-1 and reduced Akt phosphorylation in IPPKKNQDKTE-treated insulin-resistant cells.

IPPKKNQDKTE prevents high glucose-induced insulin resistance in HepG2 cells by modulating the IRS-1/PI3K/Akt signaling pathway through AMPK activation, indicating that IPPKKNQDKTE plays a potential role in the prevention and treatment of hepatic insulin resistance and type 2 diabetes.

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Does the early infant gut microbiome vary in association with a maternal high-fat diet?

Emerging evidence suggests that the in utero environment is not sterile as once presumed. Work in the mouse demonstrated transmission of commensal bacteria from mother to fetus during gestation, though it is unclear what modulates this process. We have previously shown in the nonhuman primate that, independent of obesity, a maternal high-fat diet during gestation and lactation persistently shapes the juvenile gut microbiome. We therefore sought to interrogate in a population-based human longitudinal cohort whether a maternal high-fat diet similarly alters the neonatal and infant gut microbiome in early life. A representative cohort was prospectively enrolled either in the early third trimester or intrapartum (n = 163), with a subset consented to longitudinal sampling through the postpartum interval (n = 81). Multiple body site samples, including stool and meconium, were collected from neonates at delivery and by 6 weeks of age. A rapid dietary questionnaire was administered to estimate intake of fat, added sugars, and fiber over the past month (National Health and Examination Survey). DNA was extracted from each infant meconium/stool sample (MoBio) and subjected to 16S rRNA gene sequencing and analysis. On average, the maternal dietary intake of fat ranged from 14.0 to 55.2 %, with an average intake of 33.1 % (σ = 6.1 %). Mothers whose diets significantly differed from the mean (±1 standard deviation) were separated into two distinct groups, a control group (n = 13, μ = 24.4 %) and a high-fat group (n = 13, μ = 43.1 %). Principal coordinate analysis revealed that the microbiome of the neonatal stool at birth (meconium) clustered differently by virtue of maternal gestational diet (PERMANOVA p = 0.001). LEfSe feature selection identified several taxa that discriminated the groups, with a notable relative depletion of Bacteroides in the neonates exposed to a maternal high-fat gestational diet (Student's t-test, p < 0.05) that persisted to 6 weeks of age.

Similar to the primate, independent of maternal body mass index, a maternal high-fat diet is associated with distinct changes in the neonatal gut microbiome at birth which persist through 4-6 weeks of age. Our findings underscore the importance of counseling pregnant mothers on macronutrient consumption during pregnancy and lactation.

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Does cholesterol efflux capacity of high-density lipoprotein correlate with survival and allograft vasculopathy in cardiac transplant recipients?

Cardiac allograft vasculopathy (CAV) is a major cause of mortality after cardiac transplantation. High-density lipoprotein (HDL) cholesterol efflux capacity (CEC) is inversely associated with coronary artery disease. In 2 independent studies, we tested the hypothesis that reduced CEC is associated with mortality and disease progression in CAV. We tested the relationship between CEC and survival in a cohort of patients with CAV (n = 35). To determine whether reduced CEC is associated with CAV progression, we utilized samples from the Clinical Trials in Organ Transplantation 05 (CTOT05) study to determine the association between CEC and CAV progression and status at 1 year (n = 81), as assessed by average change in maximal intimal thickness (MIT) on intravascular ultrasound. Multivariable Cox proportional hazard models demonstrated that higher levels of CEC were associated with improved survival (hazard ratio 0.26, 95% confidence interval 0.11 to 0.63) per standard deviation CEC, p = 0.002). Patients who developed CAV had reduced CEC at baseline and 1-year post-transplant. We observed a significant association between pre-transplant CEC and the average change in MIT, particularly among patients who developed CAV at 1 year (β = -0.59, p = 0.02, R

Reduced CEC is associated with disease progression and mortality in CAV patients. These findings suggest the hypothesis that interventions to increase CEC may be useful in cardiac transplant patients for prevention or treatment of CAV.

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Does exenatide induce Impairment of Autophagy Flux to Damage Rat Pancreas?

The study aimed to explore the alteration of autophagy in rat pancreas treated with exenatide. Normal Sprague-Dawley rats and diabetes-model rats induced by 2-month high-sugar and high-fat diet and streptozotocin injection were subcutaneously injected with exenatide, respectively, for 10 weeks, with homologous rats treated with saline as control. Meanwhile, AR42J cells, pancreatic acinar cell line, were cultured with exenatide at doses of 5 pM for 3 days. The pancreas was disposed, and several sections were stained with hematoxylin-eosin. Immunohistochemistry was used to measure the expressions of glucagon-like peptide 1 receptor (GLP-1R) and cysteinyl aspartate specific proteinase-3 in rat pancreas, and Western blot was used to test the expressions of GLP-1R, light chain 3B-I and -II, and p62 in rat pancreas and AR42J cells. The data were expressed as mean (standard deviation) and analyzed by unpaired Student t test using SPSS 18.0 statistics software (SPSS China, Shanghai, China). Exenatide can induce pathological changes in rat pancreas. The GLP-1R, p62, light chain 3B-II, and cysteinyl aspartate specific proteinase-3 in rat pancreas and AR42J cells treated with exenatide were significantly overexpressed.

Exenatide can activate and upregulate its receptor, GLP-1R, then impair autophagy flux and activate apoptosis in the pancreatic acinar cell, thus damaging rat pancreas.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially.

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Does an integrated community TB-HIV adherence model provide an alternative to DOT for tuberculosis patients in Cape Town?

Cape Town, South Africa. To evaluate anti-tuberculosis treatment outcomes and rate of antiretroviral therapy (ART) initiation using weekly community-based adherence support compared to daily directly observed therapy (DOT). This was a retrospective analysis comparing two cohorts treated for tuberculosis (TB) in 70 TB clinics during 6-month periods before and after the introduction of a new adherence model comprising treatment literacy sessions during 2 weeks of DOT, followed by weekly home visits by community care workers to eligible patients managing their own treatment. Odds ratios (ORs) of treatment success and ART initiation were calculated using multivariable random effects logistic regression models. Hazard ratios (HRs) of default and death were calculated using multivariable random effects Cox regression models. The pre-intervention cohort comprised 11 896 patients with TB and the post-intervention cohort 11 314. There was no difference in pre- and post-intervention anti-tuberculosis treatment success rates (respectively 82.8% and 82.5%, adjusted OR [aOR] 1.02, 95%CI 0.89-1.17, P = 0.76) nor an increased hazard of death (adjusted HR [aHR] 0.98, 95%CI 0.80-1.21, P = 0.87) or default (aHR 0.97, 95%CI 0.81-1.15, P = 0.69). The ART initiation rate increased from 67% to 74% (aOR 1.43; 95%CI 1.01-1.85, P < 0.01).

Weekly community-based adherence support was a viable alternative to daily DOT, with no deterioration in anti-tuberculosis treatment outcomes and an increase in ART initiation.

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Does next-generation sequencing survey of biliary tract cancer reveal the association between tumor somatic variants and chemotherapy resistance?

Biliary tract cancers (BTCs) are uncommon and are associated with a dismal prognosis. Combinations of gemcitabine and platinum chemotherapy (gemcitabine and platinum-based therapy [GP]) form the standard approach for treating advanced BTC. To characterize the spectrum of mutations and to identify potential biomarkers for a GP response in BTC, this study evaluated the genomic landscape and assessed whether mutations affecting DNA repair were associated with GP resistance. Pretreatment, formalin-fixed, paraffin-embedded samples from 183 BTC patients treated with GP were analyzed. Cox regression models were used to determine the association between mutations, progression-free survival (PFS), and overall survival (OS). When genes with an incidence > 10% were considered, no individual gene was independently predictive of a GP response. In patients with unresectable BTC who received GP as their first-line therapy, the joint status of cyclin-dependent kinase inhibitor 2A (CDKN2A), tumor protein 53 (TP53), and AT-rich interaction domain 1A (ARID1A) was associated with PFS (P = .0004) and OS (P ≤ .0001). Patients with mutations in CDKN2A and TP53 were identified as a poor-prognosis cohort with a median PFS of 2.63 months and a median OS of 5.22 months. Patients with mutant ARID1A, regardless of the single-mutation status of TP53 or CDKN2A, had similar outcomes. A patient who exhibited mutations in all 3 genes had a median PFS of 20.37 months, and OS was not reached.

In the largest exploratory analysis of this kind for BTC, 3 prevalent, mutually exclusive mutations represent distinct patient cohorts. These mutations are prognostic and may represent a predictive biomarker for a GP response. Prospective studies to validate these findings are needed, and they should include the incorporation of therapies that exploit the genomic instability observed with these mutations in BTC. Cancer 2016;122:3657-66. © 2016 American Cancer Society.

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